journal article research paper topics

Choose Your Test

Sat / act prep online guides and tips, 113 great research paper topics.

General Education

One of the hardest parts of writing a research paper can be just finding a good topic to write about. Fortunately we've done the hard work for you and have compiled a list of 113 interesting research paper topics. They've been organized into ten categories and cover a wide range of subjects so you can easily find the best topic for you.

In addition to the list of good research topics, we've included advice on what makes a good research paper topic and how you can use your topic to start writing a great paper.

What Makes a Good Research Paper Topic?

Not all research paper topics are created equal, and you want to make sure you choose a great topic before you start writing. Below are the three most important factors to consider to make sure you choose the best research paper topics.

#1: It's Something You're Interested In

A paper is always easier to write if you're interested in the topic, and you'll be more motivated to do in-depth research and write a paper that really covers the entire subject. Even if a certain research paper topic is getting a lot of buzz right now or other people seem interested in writing about it, don't feel tempted to make it your topic unless you genuinely have some sort of interest in it as well.

#2: There's Enough Information to Write a Paper

Even if you come up with the absolute best research paper topic and you're so excited to write about it, you won't be able to produce a good paper if there isn't enough research about the topic. This can happen for very specific or specialized topics, as well as topics that are too new to have enough research done on them at the moment. Easy research paper topics will always be topics with enough information to write a full-length paper.

Trying to write a research paper on a topic that doesn't have much research on it is incredibly hard, so before you decide on a topic, do a bit of preliminary searching and make sure you'll have all the information you need to write your paper.

#3: It Fits Your Teacher's Guidelines

Don't get so carried away looking at lists of research paper topics that you forget any requirements or restrictions your teacher may have put on research topic ideas. If you're writing a research paper on a health-related topic, deciding to write about the impact of rap on the music scene probably won't be allowed, but there may be some sort of leeway. For example, if you're really interested in current events but your teacher wants you to write a research paper on a history topic, you may be able to choose a topic that fits both categories, like exploring the relationship between the US and North Korea. No matter what, always get your research paper topic approved by your teacher first before you begin writing.

113 Good Research Paper Topics

Below are 113 good research topics to help you get you started on your paper. We've organized them into ten categories to make it easier to find the type of research paper topics you're looking for.

Arts/Culture

• Discuss the main differences in art from the Italian Renaissance and the Northern Renaissance .
• Analyze the impact a famous artist had on the world.
• How is sexism portrayed in different types of media (music, film, video games, etc.)? Has the amount/type of sexism changed over the years?
• How has the music of slaves brought over from Africa shaped modern American music?
• How has rap music evolved in the past decade?
• How has the portrayal of minorities in the media changed?

Current Events

• What have been the impacts of China's one child policy?
• How have the goals of feminists changed over the decades?
• How has the Trump presidency changed international relations?
• Analyze the history of the relationship between the United States and North Korea.
• What factors contributed to the current decline in the rate of unemployment?
• What have been the impacts of states which have increased their minimum wage?
• How do US immigration laws compare to immigration laws of other countries?
• How have the US's immigration laws changed in the past few years/decades?
• How has the Black Lives Matter movement affected discussions and view about racism in the US?
• What impact has the Affordable Care Act had on healthcare in the US?
• What factors contributed to the UK deciding to leave the EU (Brexit)?
• What factors contributed to China becoming an economic power?
• Discuss the history of Bitcoin or other cryptocurrencies  (some of which tokenize the S&P 500 Index on the blockchain) .
• Do students in schools that eliminate grades do better in college and their careers?
• Do students from wealthier backgrounds score higher on standardized tests?
• Do students who receive free meals at school get higher grades compared to when they weren't receiving a free meal?
• Do students who attend charter schools score higher on standardized tests than students in public schools?
• Do students learn better in same-sex classrooms?
• How does giving each student access to an iPad or laptop affect their studies?
• What are the benefits and drawbacks of the Montessori Method ?
• Do children who attend preschool do better in school later on?
• What was the impact of the No Child Left Behind act?
• How does the US education system compare to education systems in other countries?
• What impact does mandatory physical education classes have on students' health?
• Which methods are most effective at reducing bullying in schools?
• Do homeschoolers who attend college do as well as students who attended traditional schools?
• Does offering tenure increase or decrease quality of teaching?
• How does college debt affect future life choices of students?
• Should graduate students be able to form unions?

• What are different ways to lower gun-related deaths in the US?
• How and why have divorce rates changed over time?
• Is affirmative action still necessary in education and/or the workplace?
• Should physician-assisted suicide be legal?
• How has stem cell research impacted the medical field?
• How can human trafficking be reduced in the United States/world?
• Should people be able to donate organs in exchange for money?
• Which types of juvenile punishment have proven most effective at preventing future crimes?
• Has the increase in US airport security made passengers safer?
• Analyze the immigration policies of certain countries and how they are similar and different from one another.
• Several states have legalized recreational marijuana. What positive and negative impacts have they experienced as a result?
• Do tariffs increase the number of domestic jobs?
• Which prison reforms have proven most effective?
• Should governments be able to censor certain information on the internet?
• Which methods/programs have been most effective at reducing teen pregnancy?
• What are the benefits and drawbacks of the Keto diet?
• How effective are different exercise regimes for losing weight and maintaining weight loss?
• How do the healthcare plans of various countries differ from each other?
• What are the most effective ways to treat depression ?
• What are the pros and cons of genetically modified foods?
• Which methods are most effective for improving memory?
• What can be done to lower healthcare costs in the US?
• What factors contributed to the current opioid crisis?
• Analyze the history and impact of the HIV/AIDS epidemic .
• Are low-carbohydrate or low-fat diets more effective for weight loss?
• How much exercise should the average adult be getting each week?
• Which methods are most effective to get parents to vaccinate their children?
• What are the pros and cons of clean needle programs?
• How does stress affect the body?
• Discuss the history of the conflict between Israel and the Palestinians.
• What were the causes and effects of the Salem Witch Trials?
• Who was responsible for the Iran-Contra situation?
• How has New Orleans and the government's response to natural disasters changed since Hurricane Katrina?
• What events led to the fall of the Roman Empire?
• What were the impacts of British rule in India ?
• Was the atomic bombing of Hiroshima and Nagasaki necessary?
• What were the successes and failures of the women's suffrage movement in the United States?
• What were the causes of the Civil War?
• How did Abraham Lincoln's assassination impact the country and reconstruction after the Civil War?
• Which factors contributed to the colonies winning the American Revolution?
• What caused Hitler's rise to power?
• Discuss how a specific invention impacted history.
• What led to Cleopatra's fall as ruler of Egypt?
• How has Japan changed and evolved over the centuries?
• What were the causes of the Rwandan genocide ?

• Why did Martin Luther decide to split with the Catholic Church?
• Analyze the history and impact of a well-known cult (Jonestown, Manson family, etc.)
• How did the sexual abuse scandal impact how people view the Catholic Church?
• How has the Catholic church's power changed over the past decades/centuries?
• What are the causes behind the rise in atheism/ agnosticism in the United States?
• What were the influences in Siddhartha's life resulted in him becoming the Buddha?
• How has media portrayal of Islam/Muslims changed since September 11th?

Science/Environment

• How has the earth's climate changed in the past few decades?
• How has the use and elimination of DDT affected bird populations in the US?
• Analyze how the number and severity of natural disasters have increased in the past few decades.
• Analyze deforestation rates in a certain area or globally over a period of time.
• How have past oil spills changed regulations and cleanup methods?
• How has the Flint water crisis changed water regulation safety?
• What are the pros and cons of fracking?
• What impact has the Paris Climate Agreement had so far?
• What have NASA's biggest successes and failures been?
• How can we improve access to clean water around the world?
• Does ecotourism actually have a positive impact on the environment?
• Should the US rely on nuclear energy more?
• What can be done to save amphibian species currently at risk of extinction?
• What impact has climate change had on coral reefs?
• How are black holes created?
• Are teens who spend more time on social media more likely to suffer anxiety and/or depression?
• How will the loss of net neutrality affect internet users?
• Analyze the history and progress of self-driving vehicles.
• How has the use of drones changed surveillance and warfare methods?
• Has social media made people more or less connected?
• What progress has currently been made with artificial intelligence ?
• Do smartphones increase or decrease workplace productivity?
• What are the most effective ways to use technology in the classroom?
• How is Google search affecting our intelligence?
• When is the best age for a child to begin owning a smartphone?
• Has frequent texting reduced teen literacy rates?

How to Write a Great Research Paper

Even great research paper topics won't give you a great research paper if you don't hone your topic before and during the writing process. Follow these three tips to turn good research paper topics into great papers.

#1: Figure Out Your Thesis Early

Before you start writing a single word of your paper, you first need to know what your thesis will be. Your thesis is a statement that explains what you intend to prove/show in your paper. Every sentence in your research paper will relate back to your thesis, so you don't want to start writing without it!

As some examples, if you're writing a research paper on if students learn better in same-sex classrooms, your thesis might be "Research has shown that elementary-age students in same-sex classrooms score higher on standardized tests and report feeling more comfortable in the classroom."

If you're writing a paper on the causes of the Civil War, your thesis might be "While the dispute between the North and South over slavery is the most well-known cause of the Civil War, other key causes include differences in the economies of the North and South, states' rights, and territorial expansion."

#2: Back Every Statement Up With Research

Remember, this is a research paper you're writing, so you'll need to use lots of research to make your points. Every statement you give must be backed up with research, properly cited the way your teacher requested. You're allowed to include opinions of your own, but they must also be supported by the research you give.

#3: Do Your Research Before You Begin Writing

You don't want to start writing your research paper and then learn that there isn't enough research to back up the points you're making, or, even worse, that the research contradicts the points you're trying to make!

Get most of your research on your good research topics done before you begin writing. Then use the research you've collected to create a rough outline of what your paper will cover and the key points you're going to make. This will help keep your paper clear and organized, and it'll ensure you have enough research to produce a strong paper.

What's Next?

Are you also learning about dynamic equilibrium in your science class? We break this sometimes tricky concept down so it's easy to understand in our complete guide to dynamic equilibrium .

Thinking about becoming a nurse practitioner? Nurse practitioners have one of the fastest growing careers in the country, and we have all the information you need to know about what to expect from nurse practitioner school .

Want to know the fastest and easiest ways to convert between Fahrenheit and Celsius? We've got you covered! Check out our guide to the best ways to convert Celsius to Fahrenheit (or vice versa).

These recommendations are based solely on our knowledge and experience. If you purchase an item through one of our links, PrepScholar may receive a commission.

Christine graduated from Michigan State University with degrees in Environmental Biology and Geography and received her Master's from Duke University. In high school she scored in the 99th percentile on the SAT and was named a National Merit Finalist. She has taught English and biology in several countries.

Student and Parent Forum

Our new student and parent forum, at ExpertHub.PrepScholar.com , allow you to interact with your peers and the PrepScholar staff. See how other students and parents are navigating high school, college, and the college admissions process. Ask questions; get answers.

Ask a Question Below

Have any questions about this article or other topics? Ask below and we'll reply!

Improve With Our Famous Guides

• For All Students

The 5 Strategies You Must Be Using to Improve 160+ SAT Points

How to Get a Perfect 1600, by a Perfect Scorer

Series: How to Get 800 on Each SAT Section:

Score 800 on SAT Math

Score 800 on SAT Reading

Score 800 on SAT Writing

Series: How to Get to 600 on Each SAT Section:

Score 600 on SAT Math

Score 600 on SAT Reading

Score 600 on SAT Writing

Free Complete Official SAT Practice Tests

What SAT Target Score Should You Be Aiming For?

15 Strategies to Improve Your SAT Essay

The 5 Strategies You Must Be Using to Improve 4+ ACT Points

How to Get a Perfect 36 ACT, by a Perfect Scorer

Series: How to Get 36 on Each ACT Section:

36 on ACT English

36 on ACT Math

36 on ACT Reading

36 on ACT Science

Series: How to Get to 24 on Each ACT Section:

24 on ACT English

24 on ACT Math

24 on ACT Reading

24 on ACT Science

What ACT target score should you be aiming for?

ACT Vocabulary You Must Know

ACT Writing: 15 Tips to Raise Your Essay Score

How to Get Into Harvard and the Ivy League

How to Get a Perfect 4.0 GPA

How to Write an Amazing College Essay

What Exactly Are Colleges Looking For?

Is the ACT easier than the SAT? A Comprehensive Guide

Should you retake your SAT or ACT?

When should you take the SAT or ACT?

Stay Informed

Get the latest articles and test prep tips!

Looking for Graduate School Test Prep?

Check out our top-rated graduate blogs here:

GRE Online Prep Blog

GMAT Online Prep Blog

TOEFL Online Prep Blog

Holly R. "I am absolutely overjoyed and cannot thank you enough for helping me!”

• SAT BootCamp
• SAT MasterClass
• SAT Private Tutoring
• SAT Proctored Practice Test
• ACT Private Tutoring
• Academic Subjects
• College Essay Workshop
• Academic Writing Workshop
• AP English FRQ BootCamp
• 1:1 College Essay Help
• Online Instruction
• Free Resources

500 Good Research Paper Topics

Bonus Material: Essential essay checklist

Writing a research paper for a class and not sure how to start?

One of the most important steps to creating a great paper is finding a good topic! 

Here’s a hand-drafted list from a Princeton grad who has helped professors at Harvard and Yale edit their papers for publication and taught college writing at the University of Notre Dame and .

What’s more, we give you some foolproof formulas for creating your own paper topic to fit the requirements of your class.

Using these simple formulas, we’ve helped hundreds of students turn a B- paper topic into an A+ paper topic.

Keep reading for our list of 500 vetted research paper topics and our magic formulas for creating your own topic!

Of course, if you want help learning to write research papers tailored to your individual needs, check out our one-on-one writing coaching or academic writing workshop . Set up a free consultation to see how we can help you learn to write A+ papers!

Jump to paper topics in:

European & Mediterranean History

African history, asian history, history of the pre-columbian americas.

• Latin American History

History of Science

Politics & public policy, education & education policy, political theory, science policy.

• Health Sciences & Psychology

What is a research paper?

In order to write a good research paper, it’s important to know what it is! 

In general, we can divide academic writing into three broad categories:

• Analytical: analyze the tools an author uses to make their point
• Research: delve deeply into a research topic and share your findings
• Persuasive : argue a specific and nuanced position backed by evidence

What’s the difference between an analytical paper and a research paper? For an analytical paper, it’s okay to just use one or two sources (a book, poem, work of art, piece of music, etc.) and examine them in detail. For a research paper, however, the expectation is that you do, well . . . research .

The depth of research that you’re expected to do will depend on your age and the type of class you’re taking.

In elementary or middle school, a “research paper” might mean finding information from a few general books or encyclopedias in your school library. 

In high school, your teachers might expect you to start using information from academic articles and more specific books. You might use encyclopedias and general works as a starting point, but you’ll be expected to go beyond them and do more work to synthesize information from different perspectives or different types of sources. You may also be expected to do “primary research,” where you study the source material yourself, instead of synthesizing what other people have written about the source material.

In college, you’ll be required to use academic journals and scholarly books, and your professors will now expect that you be more critical of these secondary sources, noticing the methodology and perspectives of whatever articles and books you’re using. 

In more advanced college courses, you’ll be expected to do more exhaustive surveys of the existing literature on a topic. You’ll need to conduct primary research that makes an original contribution to the field—the kind that could be published in a journal article itself.

For a walkthrough of the 12 essential steps to writing a good paper, check out our step-by-step guide .

Working on a research paper? Grab our free checklist to make sure your essay has everything it needs to earn an A grade.

Get the essential essay checklist

What makes a good research paper topic?

One of the most important features of a research paper topic is that it has a clear, narrow focus. 

For example, your teacher may assign you to write a research paper related to the US Revolutionary War. Does that mean that your topic should be “the US Revolutionary War”? 

Definitely not! There’s no way to craft a good paper with in-depth research with such a broad topic. (Unless you’re in elementary or middle school, in which case it’s okay to have a more general topic for your research paper.)

Instead, you need to find a more specific topic within this broader one. There are endless ways that you can make this narrower! Some ideas generated from this one broader topic might be:

• Causes of the US Revolutionary War
• Changes in military strategy during the Revolutionary War
• The experiences of Loyalists to England who remained in the American colonies during the Revolutionary War
• How the Revolutionary War was pivotal for the career of Alexander Hamilton
• The role of alliances with France during the US Revolutionary War
• The experiences of people of color during the Revolutionary War
• How George Washington’s previous military career paved the way for his leadership in the Revolutionary War
• The main types of weaponry during the Revolutionary War
• Changes in clothing and fashion over the courses of the Revolutionary War
• How Valley Forge was a key moment in the Revolutionary War
• How women contributed to the Revolutionary War
• What happened in Amherst, Massachusetts during the Revolutionary War
• Field medicine during the Revolutionary War
• How the Battle of Saratoga was a turning point in the Revolutionary War
• How different opinions about the Revolutionary War were reflected in poetry written during that time
• Debates over abolition during the Revolutionary War
• The importance of supply chains during the Revolutionary War
• Reactions to the US Revolutionary war in Europe
• How the US Revolutionary war impacted political theory in England and France
• Similarities and differences between the US Revolutionary War and the French Revolution
• Famous paintings inspired by the US Revolutionary War
• Different ways that the US Revolutionary War has been depicted in modern contemporary culture
• The appropriation of the “Boston Tea Party” by US politicians in the 2010s

This list could go on forever!

In fact, any of these topics could become even more specific. For example, check out the evolution of this topic:

• Economic causes of the Revolutionary war
• The way that tax policies helped lead to the Revolutionary War
• How tax laws enacted 1763–1775 helped lead to the Revolutionary War
• How the tax-free status of the British East India Company helped lead to the Revolutionary War
• How the 1773 tax-free status of the British East India Company helped lead to the Revolutionary War, as reflected in letters written 1767–1775
• How the 1773 tax-free status of the British East India Company helped lead to the Revolutionary War, as reflected in letters written by members of the Sons of Liberty 1767–1775

As you advance in your educational career, you’ll need to make your topic more and more specific. Steps 1–3 of this topic might be okay in high school, but for a college research paper steps 4–7 would be more appropriate!

As you craft your research paper topic, you should also keep in mind the availability of research materials on your subject. There are millions of topics that would make interesting research papers, but for which you yourself might not be able to investigate with the primary and secondary sources to which you have access.

Access to research materials might look like:

• To the best of our knowledge, the sources exist somewhere
• The source isn’t behind a paywall (or you or your school can pay for it)
• Your school or local library has a copy of the source
• Your school or local library can order a copy of the source for you
• The source is in a language that you speak
• The source has been published already (there’s tons of amazing research that hasn’t been published yet, a frustrating problem!)
• You can access the archive, museum, or database where the primary source is held—this might mean online access or travel! To access a source in an archive or museum you’ll often need permission, which often requires a letter of support from your school.

If you’re not sure about access to source materials, talk to a librarian! They’re professionals for this question.

Finally, pick a research topic that interests you! Given that there are unlimited research topics in the world and many ways to adapt a broad topic, there should absolutely be a way to modify a research topic to fit your interests.

Want help learning to write an amazing research paper? Work one-on-one with an experienced Ivy-League tutor to improve your writing skills or sign up for our bestselling academic writing workshop .

Insider tips to generate your own research paper topic

Use these formulas to generate your own research paper topics:

• How did X change over a period of time (year, decade, century)?
• What is the impact (or consequences) of X?
• What led to X?
• What is the role of X in Y?
• How did X influence Y?
• How did X become Y?
• How was X different from Y?
• How is X an example of Y?
• How did X affect Y?
• What were some reactions to X?
• What are the most effective policies to produce X result?
• What are some risks of X?
• How is our current understanding of X incorrect? (advanced)
• What happens if we look at X through the lens of Y theory or perspective? (advanced)

A good research paper topic often starts with the question words—why, how, what, who, and where. Remember to make it as specific as possible!

Good research paper topics

These research paper topics have been vetted by a Princeton grad and academic book editor!

• How did European rivalries (British vs French) impact North American history?
• What was the role of British and French alliances with indigneous tribes during the Seven Years’ War?
• Reactions to the 1754 Albany Congress among North American intellectual figures
• How the Albany Plan served as a model for future attempts at union among the North American colonies
• How did different religious identities (Calvinist, Catholic, etc.) play a role in the aftermath of the Seven Years’ War?
• What were the consequences of the 1763 Treaty of Paris?
• How did the Seven Years’ War impact British debt and colonial economics?
• What were some causes of the US Revolutionary War?
• How did military strategy change during the Revolutionary War?
• What were the experiences of Loyalists to England who remained in the American colonies during the Revolutionary War?
• How was the Revolutionary War pivotal for the career of Alexander Hamilton?
• What was the role of alliances with France during the US Revolutionary War?
• What were the experiences of people of color during the Revolutionary War?
• How did George Washington’s previous military career pave the way for his leadership in the Revolutionary War?
• What were the main types of weaponry during the Revolutionary War? How did that affect the options for military strategies?
• How did clothing and fashion change over the courses of the Revolutionary War?
• How was Valley Forge a key moment in the Revolutionary War?
• How did women contribute to the Revolutionary War?
• What happened in Amherst, Massachusetts (or any other specific location) during the Revolutionary War?
• What was field medicine like during the Revolutionary War? 
• How was the Battle of Saratoga a turning point in the Revolutionary War?
• How were different opinions about the Revolutionary War reflected in poetry written during that time?
• What were the debates over abolition during the Revolutionary War?
• What was the role of supply chains during the Revolutionary War?
• What were reactions to the US Revolutionary war like in Europe? What does that tell us about politics in England, France, the Netherlands, etc?
• How did the US Revolutionary war impact political theory in England and France?
• What are similarities and differences between the US Revolutionary War and the French Revolution?
• What are some famous paintings inspired by the US Revolutionary War? What do differences between these paintings tell us about how the artists who created them saw the war?
• What are some different ways that the US Revolutionary War has been depicted in modern contemporary culture? What does that tell us?
• How was the story of the “Boston Tea Party” appropriated by US politicians in the 2010s, and why?
• What was the difference between the Federalists and the Jeffersonians?
• How did the 1797 XYZ Affair lead to the Quasi-War with France?
• How were loans from European countries and companies (France, Spain, Dutch bankers) key to the early US?
• What were reactions to the Constitutional Convention of 1787?
• Why did the US remain neutral during the French Revolution?
• How did the Alien and Sedition acts contribute to the election of Thomas Jefferson as president?
• What was the US’s reaction to the Haitian revolution? Why did the US not recognize Haitian independence until 1862?
• What were the reactions to John Jay’s Treaty of 1794?
• How have the remarks made by George Washington in his Farewell Address inspired isolationist policies?
• How did interpretations of the Monroe Doctrine change over the decades since its creation? 
• How did the Roosevelt Corollary and Lodge Corollary change and expand the Monroe Doctrine?
• How did the presence of US companies like the United Fruit Company affect US military interventions in Latin America? 
• How was the Monroe Doctrine invoked in the Cuban Missile Crisis of 1962? 
• How was US culture shaped by the Cold War?
• How did ecology play a role in the rise of Ancient Egypt?
• How did water management technologies impact Ancient Egypt?
• How did bureaucracies function in Ancient Egypt?
• How did Egyptian art influence Ancient Greek art?
• Who could be a citizen in Athens in the 5th century BCE? What does this tell us about classical Athenian society?
• What was the impact of the Peloponnesian War?
• What was the impact of Alexander the Great’s attempt to create an empire?
• How does the way that Alexander the Great is represented in art demonstrate conceptions about the relationship between the human and the divine?
• Was there a conception of race in the ancient world? How were these ideas different from our own modern conceptions of race?
• What was the role of debt slavery in the Roman republic? How were these policies ended, and what is the significance of the end of debt slavery? What kinds of slavery remained?
• To what degree does the movie Gladiator accurately the Roman Empire in 176–192 CE?
• What was the role of slavery in managing the large latifundia ?
• How and why did the emperor Constantine I adopt Christianity?
• How did patterns of urbanism in the latter Roman empire change? What does this tell us about challenges being faced at that time?
• What do reactions to the Byzantine empress Theodora tell us about ideas of gender in 6th-century Byzantium?
• How did scientific advancements in Islamic Spain influence the rest of Europe?
• What was the relationship between Muslim, Christian, and Jewish populations in Islamic Spain? How does this compare to the experience of Muslim and Jewish populations in Christian Spain?
• How did medieval troubadour poetry represent a new idea of romantic relationships?
• What are similarities and differences between medieval troubadour poetry and lyric poetry in Ancient Greece? 
• What do letters between women and popes tell us about gender, power, and religion in medieval Europe?
• In what ways was Hildegard of Bingen groundbreaking for her time?
• Who produced beer in medieval England, and what does this tell us about society?
• How did the adoption of hops affect the production and distribution of beer?
• How did beer production allow some women a way to be financially independent?
• How was clothing used to mark religious and cultural identities in 15th- and 16th-century Spain?
• How did print culture change relationships and courting in Georgian England?
• How did churches function as social gathering spaces in Georgian England?
• To what degree is Netflix’s Bridgerton series historically accurate?
• How did ideas of love change in the 18th century? How did philosophy play a role in this?
• When were Valentine cards first commercially available? What does that show us about cultural ideas of love and courtship?
• What were the consequences of the desertification of the Sahara?
• How did trade links on the Red Sea influence Nubian culture?
• How did Carthage build power in Northern Africa around 600–500 BCE?
• What was the impact of the Mercenary War (241–238 BCE) in Carthage?
• How did the Roman province of Africa play a key role in financing the Roman Empire?
• What were the consequences of the Donatist division in the 300s in Northern Africa?
• What was the impact of the large-scale movement of Bedouins from the Arabian peninsula into the Maghreb?
• How was Mande society organized in the Mali Empire? 
• What was the role of the book trade in Timbuktu? What does this tell us about culture and learning in the Mali Empire?
• How did Aksum use trade to build wealth and power? 
• What do Nok terracotta sculptures tell us about Nok culture?
• How did the Luba Empire create a centralized political system? How did the idea of spiritual kins ( balopwe ) play a role in this system?
• How did tax collection work in the Lunda empire?
• What does it mean to say that the Ajuran Empire was a hydraulic empire? How did control over water resources allow the Ajuran Empire to build and consolidate power?
• What is the significance of diplomatic ties between the Somai Ajuran Empire and Ming dynasty China? 
• How did the tribute system in the Kingdom of Kongo help to stimulate interregional trade?
• What was the impact of the introduction of maize and cassava to the Kingdom of Kongo?
• How did women wield influence in the Kingdom of Benin?
• How did the Industrial Revolution in Europe help lead to the Scramble for Africa 1878–1898?
• What were the consequences of the Second Boer War?
• What happened in the Year of Africa (1960)?
• How did the Han dynasty consolidate power in frontier regions? 
• How and why did the Han dynasty nationalize the private salt and iron industries in 117 BCE?
• What are the earliest records of papermaking, and what is the significance of this invention?
• What was the role of Daoist religious societies in rebellions at the end of the Han dynasty (Yellow Turban Rebellion, Five Pecks of Rice Rebellion)?
• What do tomb paintings tell us about ancient Chinese society?
• What was the impact of the Sui dynasty’s standardization and re-unification of the coinage?
• What was the role of standardized testing in Sui dynasty and Tang dynasty China?
• Why is the Tang dynasty often regarded as a golden age of cosmopolitan culture in Chinese history?
• What was the role of slavery in imperial China? 
• How did the rise of jiedushi (regional military governments) undermine the civil-service system? What were the consequences of this?
• How did Tang dynasty China exert power over Japan and Korea?
• What was the Three Departments and Six Ministries system in imperial China and how did it work?
• What does the appearance of Inca, Maya, and Aztec goods in North America (Utah, Canada) and the appearance of goods from the Great Lakes region in Maya and Aztec ruins tell us about trade in the Pre-Columbian Americas?
• How did celebration of maize play a central role in Mesoamerican cultures?
• How did the Aztec empire use relationships with client city-states to establish power? How did the Aztec empire use taxation to exert power?
• How did the luxury good trade impact Aztec political power? 
• How did the building of roads play a key role in the Aztec empire?
• How and why has archaeology played a pivotal role in expanding our understanding of the pre-Columbian Americas?
• What are some common misconceptions about the Americas in the year 1491? Why do these misconceptions exist?

Latin American History (post-1492)

• How and why did the Spanish appropriate Aztec sites of significance (e.g. Mexico City at the site of Tenochtitlan)?
• What were reactions among Latin American intellectuals (e.g. Luis María Drago, Alejandro Álvarez and Baltasar Brum) to the Monroe Doctrine?
• How was the US’s involvement in the Venezuela Crisis of 1902–1903 a pivotal turning point in the relationship between the US and Latin American countries?
• What were the effects of the US’s involvement in the Cuban War for Independence?
• How did the Roosevelt Corollary of 1904 benefit the US?
• How did Simon Bolivar’s time in Europe affect his ideas about Latin American independence?
• How did 19th century academic societies play a role in the advancement of scientific discoveries? Who was excluded from these societies?
• How was music connected to the sciences in medieval thinking?
• When was the concept of zero first used, and how was it instrumental for advancements in math?
• What role did Islamic Spain play in the spread of scientific advancements in medieval Europe?
• What role has translation between languages played in the development of sciences?
• Why were Galileo’s ideas about astronomy controversial at the time?
• What was the connection between art and advancements in human anatomy?
• Why were Darwin’s ideas about natural selection controversial at the time?
• To what degree does the film Master and Commander accurately depict the voyages of Charles Darwin?
• How did the discovery of quinine and other medical innovations help to facilitate the European colonization of Africa?
• How and why was the internet invented?
• Does Virgil’s Aeneid celebrate the new Roman Empire or subvert it?
• Why was the poet Ovid exiled from Rome?
• What are the pagan influences in Beowulf ? What are the Christian elements in Beowulf ? What does that tell us about late Anglo-Saxon England?
• How does Chaucer’s Canterbury Tales reflect gender roles in late medieval England?
• How does Dante’s Inferno draw on book IV of Virgil’s Aeneid ? 
• How are gender roles presented and subverted in Shakespeare’s plays?
• To what degree did Henry David Thoreau live out the ideals he described in Walden in his own life?
• How did the serialized publication of novels affect the way that they were written?
• Does Dickens’ novel A Tale of Two Cities accurately portray the French Revolution?
• How did 18th-century novels propagate the idea of marrying for love?
• What did contemporary readers think about Jane Austen and her novels?
• To what degree do Jane Austen’s novels reflect economic realities for women in Regency England? What do they leave out?
• How did Lord Byron’s personal life affect his poetry?
• What do we know about the romantic life of Emily Dickinson?
• What were the religious movements that influenced the writer George Eliot, and how do those influences appear in her novels?
• In what ways were Walt Whitman’s writings new or different?
• How did British poets react to the horrors of Word War I?
• What do Tolkien’s letters reveal about the ways in which the two world wars influenced his writings?
• How did the friendship between CS Lewis and Tolkien affect their respective writings?
• What are the arguments for and against Catalonian independence from Spain?
• What are the arguments for and against Scottish independence from the United Kingdom?
• What are some risks of contact sports, especially for children?
• What are the most effective policies for combating childhood obesity?
• What are the most effective policies for reducing gun violence?
• Which countries have the longest life expectancy and why?
• What are some differences between the healthcare system in the US and in European countries? Which country has the most similar system to the US?
• What policies for parental leave exist in different countries? What are some effects of these policies?
• Has the drinking age in the US always been 21? What have been some different policies, and what were some consequences of them?
• What is the debate around museum artifacts like the Elgin Marbles in London or the Benin Bronzes in Berlin?
• How have politicians attempted to control population growth in different countries, either directly or indirectly? What have been some effects of these policies?
• Which countries have the most gender parity reflected in national governments? How have they accomplished this?
• How has public funding of K-12 education changed since the 1930s in the US? 
• How has public funding of higher education changed in the US?
• What is early childhood education like in different countries?
• What are some effects of free or reduced-cost meals in schools?
• How does access to menstrual products affect education outcomes for girls in different countries?
• What was the impact of Rousseau’s writings on education?
• How did Plato’s ideal forms of government reflect contemporary Athenian concerns about the unruly masses ( demos )?
• How did Aristotle justify slavery?
• How has wealth inequality increased in recent decades?
• How is inflation calculated, and what are the implications of this methodology?
• How have genetically-engineered crops changed the way that the planet feeds itself?
• How has animal testing changed since 2000?
• How is animal testing regulated differently in different countries?

Health Sciences and Psychology

• How do different societies reflect the natural circadian rhythms of the human body?
• How does secondhand smoke affect the human body?
• How does lack of sleep affect the body?
• How does stress affect the body?
• What are some ways to reduce stress?
• How have cancer treatments changed in the past 30 years?
• Why is it hard to find a “cure” for cancer?
• How has the Human Genome Project changed medical science?
• How were the Covid vaccines developed so quickly? What is the difference between the various Covid vaccines that have been developed?

Ready to start working on your research paper?

Our Ivy-League tutors can provide one-on-one writing coaching . Get expert help in selecting a topic that fits your assignment, finding research sources, creating an outline, drafting your paper, and revising for clarity.

Our writing coaches have helped students turn B- papers to A+ papers with just a few sessions together. We have experience working with students of all ages and writing abilities, from middle school students to college students at the nation’s top universities. What’s more, we’ll teach you how to write so that it’s easier the next time around!

A few times per year we also offer our bestselling academic writing workshop . Save your spot here !

Related posts

99 Great Handpicked Ideas for Argumentative Essays 12 Essential Steps for Writing an Argumentative Essay The 13 SAT and ACT Grammar Rules to Know 16 Essential Literary Devices to Know

Emily graduated  summa cum laude  from Princeton University and holds an MA from the University of Notre Dame. She was a National Merit Scholar and has won numerous academic prizes and fellowships. A veteran of the publishing industry, she has helped professors at Harvard, Yale, and Princeton revise their books and articles. Over the last decade, Emily has successfully mentored hundreds of students in all aspects of the college admissions process, including the SAT, ACT, and college application essay. 

CHECK OUT THESE RELATED POSTS

15 Best ACT Tutoring Services for 2024 (75 Tutoring Services Reviewed)

April 18, 2024

A list of the 15 best online ACT tutoring services, reviewed and ranked. Compare prices & instructor qualifications. Best overall: PrepMaven’s SAT tutoring ($79–349/hr). Best on a budget: Wyzant ($20–600/hr). Best…

How to Transfer Colleges

April 11, 2024

The college transfer process is different from what you went through in high school to get into college. We’ll walk you through important steps in your application …

Varsity Tutors Review

Comprehensive review of Varsity Tutors: pricing, instructor qualifications, online platform, customer service, and educational quality.

15 Best PSAT Tutoring Services for 2024 (75 Tutoring Services Reviewed)

April 10, 2024

A list of the 13 best online SSAT tutoring services, reviewed and ranked. Compare prices & quality. Best overall: PrepMaven. Best self-guided: Test Innovators. Best on a budget...

16 Best Online Tutoring Services — Reviewed & Ranked by an Ivy-League Expert

April 9, 2024

A list of the 16 best online tutoring services, reviewed and ranked by an Ivy-League expert. Compare prices & tutor qualifications. Best overall: PrepMaven’s writing tutoring ($66–349/hr). Best on a budget: Wyzant ($20–600/hr). Best…

17 Best Online Math Tutoring Services — Reviewed & Ranked by an Ivy-League Educator

A list of the 17 best online math tutoring services, reviewed and ranked by an Ivy-League educator. Compare prices & tutor qualifications. Best overall: PrepMaven’s writing tutoring ($66–349/hr). Best on a budget: Wyzant ($20–600/hr). Best…

Should You Transfer Colleges?

April 4, 2024

If you’re thinking about transferring colleges, there’s a lot you should think about. Not all reasons for transferring are great ones: read on to learn about good reasons to transfer, bad reasons to transfer, and…

How to Request your High School Transcript

You may need to get a copy of your high school transcript for college applications, scholarship competitions, or just for your own records. Learn the most efficient way to receive your high school transcript and …

13 Best SSAT Tutoring Services for 2024 (36 Services Reviewed)

March 29, 2024

15 Best Online SAT Tutoring Services for 2024 (75 Tutoring Services Reviewed)

A list of the 15 best online SAT tutoring services, reviewed and ranked. Compare prices & instructor qualifications. Best overall: PrepMaven’s SAT tutoring ($79–349/hr). Best on a budget: Wyzant ($20–600/hr). Best…

Privacy Preference Center

Privacy preferences.

• Bipolar Disorder
• Therapy Center
• When To See a Therapist
• Types of Therapy
• Best Online Therapy
• Best Couples Therapy
• Best Family Therapy
• Managing Stress
• Sleep and Dreaming
• Understanding Emotions
• Self-Improvement
• Healthy Relationships
• Student Resources
• Personality Types
• Guided Meditations
• Verywell Mind Insights
• 2023 Verywell Mind 25
• Mental Health in the Classroom
• Editorial Process
• Meet Our Review Board
• Crisis Support

50+ Research Topics for Psychology Papers

How to Find Psychology Research Topics for Your Student Paper

Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

Steven Gans, MD is board-certified in psychiatry and is an active supervisor, teacher, and mentor at Massachusetts General Hospital.

• Specific Branches of Psychology
• Topics Involving a Disorder or Type of Therapy
• Human Cognition
• Human Development
• Critique of Publications
• Famous Experiments
• Historical Figures
• Specific Careers
• Case Studies
• Literature Reviews
• Your Own Study/Experiment

Are you searching for a great topic for your psychology paper ? Sometimes it seems like coming up with topics of psychology research is more challenging than the actual research and writing. Fortunately, there are plenty of great places to find inspiration and the following list contains just a few ideas to help get you started.

Finding a solid topic is one of the most important steps when writing any type of paper. It can be particularly important when you are writing a psychology research paper or essay. Psychology is such a broad topic, so you want to find a topic that allows you to adequately cover the subject without becoming overwhelmed with information.

I can always tell when a student really cares about the topic they chose; it comes through in the writing. My advice is to choose a topic that genuinely interests you, so you’ll be more motivated to do thorough research.

In some cases, such as in a general psychology class, you might have the option to select any topic from within psychology's broad reach. Other instances, such as in an  abnormal psychology  course, might require you to write your paper on a specific subject such as a psychological disorder.

As you begin your search for a topic for your psychology paper, it is first important to consider the guidelines established by your instructor.

Research Topics Within Specific Branches of Psychology

The key to selecting a good topic for your psychology paper is to select something that is narrow enough to allow you to really focus on the subject, but not so narrow that it is difficult to find sources or information to write about.

One approach is to narrow your focus down to a subject within a specific branch of psychology. For example, you might start by deciding that you want to write a paper on some sort of social psychology topic. Next, you might narrow your focus down to how persuasion can be used to influence behavior .

Other social psychology topics you might consider include:

• Prejudice and discrimination (i.e., homophobia, sexism, racism)
• Social cognition
• Person perception
• Social control and cults
• Persuasion, propaganda, and marketing
• Attraction, romance, and love
• Nonverbal communication
• Prosocial behavior

Psychology Research Topics Involving a Disorder or Type of Therapy

Exploring a psychological disorder or a specific treatment modality can also be a good topic for a psychology paper. Some potential abnormal psychology topics include specific psychological disorders or particular treatment modalities, including:

• Eating disorders
• Borderline personality disorder
• Seasonal affective disorder
• Schizophrenia
• Antisocial personality disorder
• Profile a  type of therapy  (i.e., cognitive-behavioral therapy, group therapy, psychoanalytic therapy)

Topics of Psychology Research Related to Human Cognition

Some of the possible topics you might explore in this area include thinking, language, intelligence, and decision-making. Other ideas might include:

• False memories
• Speech disorders
• Problem-solving

Topics of Psychology Research Related to Human Development

In this area, you might opt to focus on issues pertinent to  early childhood  such as language development, social learning, or childhood attachment or you might instead opt to concentrate on issues that affect older adults such as dementia or Alzheimer's disease.

Some other topics you might consider include:

• Language acquisition
• Media violence and children
• Learning disabilities
• Gender roles
• Child abuse
• Prenatal development
• Parenting styles
• Aspects of the aging process

Do a Critique of Publications Involving Psychology Research Topics

One option is to consider writing a critique paper of a published psychology book or academic journal article. For example, you might write a critical analysis of Sigmund Freud's Interpretation of Dreams or you might evaluate a more recent book such as Philip Zimbardo's  The Lucifer Effect: Understanding How Good People Turn Evil .

Professional and academic journals are also great places to find materials for a critique paper. Browse through the collection at your university library to find titles devoted to the subject that you are most interested in, then look through recent articles until you find one that grabs your attention.

Topics of Psychology Research Related to Famous Experiments

There have been many fascinating and groundbreaking experiments throughout the history of psychology, providing ample material for students looking for an interesting term paper topic. In your paper, you might choose to summarize the experiment, analyze the ethics of the research, or evaluate the implications of the study. Possible experiments that you might consider include:

• The Milgram Obedience Experiment
• The Stanford Prison Experiment
• The Little Albert Experiment
• Pavlov's Conditioning Experiments
• The Asch Conformity Experiment
• Harlow's Rhesus Monkey Experiments

Topics of Psychology Research About Historical Figures

One of the simplest ways to find a great topic is to choose an interesting person in the  history of psychology  and write a paper about them. Your paper might focus on many different elements of the individual's life, such as their biography, professional history, theories, or influence on psychology.

While this type of paper may be historical in nature, there is no need for this assignment to be dry or boring. Psychology is full of fascinating figures rife with intriguing stories and anecdotes. Consider such famous individuals as Sigmund Freud, B.F. Skinner, Harry Harlow, or one of the many other  eminent psychologists .

Psychology Research Topics About a Specific Career

​Another possible topic, depending on the course in which you are enrolled, is to write about specific career paths within the  field of psychology . This type of paper is especially appropriate if you are exploring different subtopics or considering which area interests you the most.

In your paper, you might opt to explore the typical duties of a psychologist, how much people working in these fields typically earn, and the different employment options that are available.

Topics of Psychology Research Involving Case Studies

One potentially interesting idea is to write a  psychology case study  of a particular individual or group of people. In this type of paper, you will provide an in-depth analysis of your subject, including a thorough biography.

Generally, you will also assess the person, often using a major psychological theory such as  Piaget's stages of cognitive development  or  Erikson's eight-stage theory of human development . It is also important to note that your paper doesn't necessarily have to be about someone you know personally.

In fact, many professors encourage students to write case studies on historical figures or fictional characters from books, television programs, or films.

Psychology Research Topics Involving Literature Reviews

Another possibility that would work well for a number of psychology courses is to do a literature review of a specific topic within psychology. A literature review involves finding a variety of sources on a particular subject, then summarizing and reporting on what these sources have to say about the topic.

Literature reviews are generally found in the  introduction  of journal articles and other  psychology papers , but this type of analysis also works well for a full-scale psychology term paper.

Topics of Psychology Research Based on Your Own Study or Experiment

Many psychology courses require students to design an actual psychological study or perform some type of experiment. In some cases, students simply devise the study and then imagine the possible results that might occur. In other situations, you may actually have the opportunity to collect data, analyze your findings, and write up your results.

Finding a topic for your study can be difficult, but there are plenty of great ways to come up with intriguing ideas. Start by considering your own interests as well as subjects you have studied in the past.

Online sources, newspaper articles, books , journal articles, and even your own class textbook are all great places to start searching for topics for your experiments and psychology term papers. Before you begin, learn more about  how to conduct a psychology experiment .

What This Means For You

After looking at this brief list of possible topics for psychology papers, it is easy to see that psychology is a very broad and diverse subject. While this variety makes it possible to find a topic that really catches your interest, it can sometimes make it very difficult for some students to select a good topic.

If you are still stumped by your assignment, ask your instructor for suggestions and consider a few from this list for inspiration.

• Hockenbury, SE & Nolan, SA. Psychology. New York: Worth Publishers; 2014.
• Santrock, JW. A Topical Approach to Lifespan Development. New York: McGraw-Hill Education; 2016.

By Kendra Cherry, MSEd Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Trending Articles

• ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion. Deng S, et al. Cell. 2024. PMID: 38614099
• Dual-role transcription factors stabilize intermediate expression levels. He J, et al. Cell. 2024. PMID: 38631355
• Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism. Chen X, et al. Nat Aging. 2024. PMID: 38627524
• Brain endothelial GSDMD activation mediates inflammatory BBB breakdown. Wei C, et al. Nature. 2024. PMID: 38632402
• Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. Choueiri TK, et al. N Engl J Med. 2024. PMID: 38631003 Clinical Trial.

Latest Literature

• Am J Clin Nutr (1)
• Diabetes Care (1)
• Gastroenterology (2)
• J Biol Chem (10)
• J Neurosci (2)
• Nature (11)
• Nucleic Acids Res (1)
• PLoS One (2)

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Finding a Paper Topic

What are the blogs talking about, what current awareness sources should i know about, what's being discussed in the academic journals, what have other dissertations or papers covered, how do i find a faculty advisor, refining your topic, getting help, how to use this guide.

This guide is aimed at law students, primarily LL.M.s, beginning the process of finding and narrowing a topic for a research paper.

Paper topic ideas may come from your lectures or course readings. Topics might come from your previous studies, work history or life experience. But, sometimes your initial subject idea is too broad, or you are interested in multiple subject areas. This guide will walk you though sources which will help you gain a sense of legal developments (if any) on your subject. It will also list sources that help you begin to find the academic conversation happening on a topic.

By browsing, searching, and reading broadly in these sources, you will hopefully find a topic that is deeply interesting to you. Enough so that you will stay engaged and motivated during the entirety of the writing process.

For HLS LL.M.s, this guide will provide links to sources from the Graduate Program which will help you determine if your topic is sufficiently narrow. It concludes with suggestions about how to identify possible HLS faculty supervisors.

Once you have decided on your topic, it is an appropriate time to request a research consult with a librarian. They can assist you by identifying targeted research sources and search strategies.

Using Blogs for Paper Topics

Blogs can be helpful to see what is "hot" in a particular field of law on a more current basis than traditional scholarly sources such as books or law review articles. You can browse them by topic area or run searches for some of your initial ideas.

Blog/Blawg Directories

• Justia's Blawg Search This is one of the largest aggregators of legal blogs. Browse by topic or search and reset the order of results by date to find the newest discussions.
• Legal Blogs via Westlaw (HLS only) Westlaw provides searchable access to over 200 law-related blogs. Topics cover almost all areas of US law, international law, and good coverage of Canadian law.
• Law Professor Blogs Network This is a collection of approximately 100 blogs authored by law professors.

Specialized News Databases

Legal news sites will alert you to interesting litigation and policy developments. Like browsing blogs, legal news sources can help you identify legal developments that might serve as a good topic.   

• Lexis Legal News Hub (HLS only) Legal news from multiple publishers including Law360.
• Law.com (HLS only) Very current, short news items about legal developments in law and the legal industry.
• Bloomberg Law News and Topic Selection Page (HLS Only) This page links to Bloomberg news offerings, and uniquely, coverage of “circuit splits”. A circuit split is when federal appellate courts are reaching different outcomes on the same topic of law. Current circuit splits can make interesting paper topics.

Legal Updates from Law Firms

Law firms often post public entries of interest to potential clients. These marketing materials are usually well crafted and cover new developments. The following sites aggregate this content for collective searching.

• vLex Justis current news The home screen offers a combination of news and updates from major law firms from LexBlog, JD Supra, and Mondaq. Use the International News option for coverage of 100 countries.

Google Scholar

Using Google can be a good starting point, but using Google Scholar is a more efficient way to find academic content. Even better, using Harvard Google Scholar will (usually) allow you to link through to content available to you through Harvard Library subscriptions.

• Harvard Google Scholar Using Google Scholar with your HarvardKey allows you to make the most of provided links, granting access to full text available through Harvard Library subscriptions.
• Google Alerts

Working Papers Repositories

After browsing widely through current awareness services for ideas, hopefully you’re starting to have a few possible topics. Digging into working papers is a good next step in comparing your topic options. Working paper repositories host collections of scholarly articles. They include those not yet published or in final form. The benefit of searching in working paper repositories is to gain a sense of the current academic conversation on a topic.

• SSRN (Social Science Research Network) SSRN is one of the most heavily used working paper sites for law professors. It is a public site but using this Harvard-affiliated access through HOLLIS will allow you to set up an individual account and subscribe to email alerts.
• Law Commons This open access working paper site is easy to browse by topic, author, and institutional affiliation.
• NBER Working Papers The National Bureau of Economic Research hosts working papers related to finance, banking, and law and economics.
• EconPapers (RePEc)
• OSF Preprints Multidisciplinary repository more global in scope than those listed above.

Law Journal Articles

As you explore possible topics, beyond searching through current sources, it's important to explore the published literature on the topic. This is the stage where you are both refining your topic and beginning your research.

There are many sources to find law journal articles. Below are some of the main collections of legal literature and good starting points. Be aware that these collections are very large. Putting in one or two search terms may result in large result lists, so consider searching with multiple keywords, phrases, etc. For assistance with advanced search techniques, please Ask a Librarian .

• Hein Online Law Journal Library (Harvard Key) Provides pdf format for law review articles in 3200 law journals. For most, coverage is from inception. Includes a good collection of non-U.S. journals.
• Lexis+ Law Reviews and Journals (HLS Only)
• Westlaw Law Reviews & Journals (HLS Only)
• LegalTrac Topic Finder (HLS) LegalTrac is an index (descriptions of articles) and has some full text. It is included here for its topic finder tool which allows you to put in some general topics, and then refine the terms to generate a list of linked articles.

Academic Articles, Books and Book Chapters

It is beyond the scope of this guide to cover specialized sources for non-U.S. and International law and legal literature. Neither does this guide cover sources for law-related literature, such as the literature of political science, economics, gender studies, etc. To find academic journal content across disciplines, the best starting point is to use HOLLIS.

• HOLLIS Catalog and Articles Beyond finding the books, ebooks, and journals owned by the Harvard Library system, using HOLLIS in its default mode (Catalog & Articles) allows you to find articles from many subscription sources. Before settling on a paper topic, running some searches in HOLLIS is a must.

Dissertations, Theses and Papers

As you refine your topic ideas, it is often helpful to browse the titles of dissertations and papers by SJDs, LLMs, or JD students, either generally, or those which touch on your subject area. This can help you understand how people have framed their research topic in a discrete, specific way. See additional sources for student-authored works in  HLS Dissertations, Theses and Third Year Papers .

• HLS LL.M. Papers in HOLLIS To refine these search results by topic, faculty advisor, seminar or date, click Add a New Line.
• HLS SJD Dissertations
• Proquest Dissertations and Theses (Harvard Key) This database includes dissertations and theses from many academic institutions but has not included HLS SJD dissertations or LL.M. papers in recent years.

Tips on Finding a Faculty Advisor

LL.M. written work requires faculty supervision. The following sources will help you identify HLS faculty members by research interests. You can also view HOLLIS records of LL.M. papers to identify the HLS professors who supervised papers in your subject area.

• HLS Faculty Directory The directory can be searched by keyword or filtered by area of interest and by categories of appointment. Directory pages usually include courses taught, publications, and research interest area. Note that some professors are here for only part of the year. Faculty supervisors must have a teaching appointment in the semester in which the paper is to be turned in.
• HLS Course Catalog This is the best source to determine who is currently teaching in your topic subject area.
• HLS Faculty Bibliography This is a collective list of publications of the HLS faculty covering recent years.
• HLS Programs of Study Programs of study are course grouping suggestions for students who want to focus their academic and career development within a field of law. Each program lists HLS faculty members associated with that field of law.

Tips for Refining a Topic

As you’ve browsed blogs, news, law reviews and other LL.M. papers, you have hopefully arrived at some topic ideas that are original and will hold your continued interest as you write the paper. It is also important to refine your paper topic to a discrete, narrow idea. Resources to help you make sure your topic is sufficiently narrow are included in the HLS Graduate Program Writing Resources Canvas Site . See especially: 

• The Six-Point Exercise in the module “Developing Your Proposal and Drafting Your Paper”
• Worksheets for Senior Thesis Writers and Others in the module “Recommended Materials on Writing”
• Archetypal Legal Scholarship: A Field Guide, 63 J. Legal Educ. 65 (2013) HLS Prof. Minow's article defines the different types of papers in the legal literature. It is helpful to read her framework as you finalize your paper topic.
• Academic Legal Writing Law Review Articles, Student Notes, Seminar Papers, and Getting on Law Review UCLA Prof. Eugene Volokh's book is a good resource as you begin a writing project. Specifcally, the section on Choosing a Claim is worth scanning before finalizing your topic.
• This publicly available excerpt from a prior edition of Volokh's book contains the chapter on Choosing a Claim. See the section beginning on page 25.

Contact Us!

  Ask Us!  Submit a question or search our knowledge base.

Chat with us!  Chat   with a librarian (HLS only)

Email: [email protected]

 Contact Historical & Special Collections at [email protected]

  Meet with Us   Schedule an online consult with a Librarian

Hours  Library Hours

Classes  View  Training Calendar  or  Request an Insta-Class

 Text  Ask a Librarian, 617-702-2728

 Call  Reference & Research Services, 617-495-4516

• Last Updated: Apr 12, 2024 4:50 PM
• URL: https://guides.library.harvard.edu/law/findingapapertopic

Harvard University Digital Accessibility Policy

2019 Best Papers published in the Environmental Science journals of the Royal Society of Chemistry

In 2019, the Royal Society of Chemistry published 180, 196 and 293 papers in Environmental Science: Processes & Impacts , Environmental Science: Water Research & Technology , and Environmental Science: Nano , respectively. These papers covered a wide range of topics in environmental science, from biogeochemical cycling to water reuse to nanomaterial toxicity. And, yes, we also published papers on the topic of the environmental fate, behavior, and inactivation of viruses. 1–10 We are extremely grateful that so many authors have chosen our journals as outlets for publishing their research and are equally delighted at the high quality of the papers that we have had the privilege to publish.

Our Associate Editors, Editorial Boards, and Advisory Boards were enlisted to nominate and select the best papers from 2019. From this list, the three Editors-in-Chief selected an overall best paper from the entire Environmental Science portfolio. It is our pleasure to present the winners of the Best Papers in 2019 to you, our readers.

Overall Best Paper

In this paper, Johansson et al. examine sea spray aerosol as a potential transport vehicle for perfluoroalkyl carboxylic and sulfonic acids. The surfactant properties of these compounds are well known and, in fact, key to many of the technical applications for which they are used. The fact that these compounds are enriched at the air–water interface makes enrichment in sea spray aerosols seem reasonable. Johansson et al. systematically tested various perfluoroalkyl acids enrichment in aerosols under conditions relevant to sea spray formation, finding that longer chain lengths lead to higher aerosol enrichment factors. They augmented their experimental work with a global model, which further bolstered the conclusion that global transport of perfluoroalkyl acids by sea spray aerosol is and will continue to be an important process in determining the global distribution of these compounds.

Journal Best Papers

Environmental Science: Processes & Impacts

First Runner-up Best Paper: Yamakawa, Takami, Takeda, Kato, Kajii, Emerging investigator series: investigation of mercury emission sources using Hg isotopic compositions of atmospheric mercury at the Cape Hedo Atmosphere and Aerosol Monitoring Station (CHAAMS), Japan , Environ. Sci.: Processes Impacts , 2019, 21 , 809–818, DOI: 10.1039/C8EM00590G .

Second Runner-up Best Paper: Avery, Waring, DeCarlo, Seasonal variation in aerosol composition and concentration upon transport from the outdoor to indoor environment , Environ. Sci.: Processes Impacts , 2019, 21 , 528–547, DOI: 10.1039/C8EM00471D .

Best Review Article: Cousins, Ng, Wang, Scheringer, Why is high persistence alone a major cause of concern? Environ. Sci.: Processes Impacts , 2019, 21 , 781–792, DOI: 10.1039/C8EM00515J .

Environmental Science: Water Research & Technology

First Runner-up Best Paper: Yang, Lin, Tse, Dong, Yu, Hoffmann, Membrane-separated electrochemical latrine wastewater treatment , Environ. Sci.: Water Res. Technol. , 2019, 5 , 51–59, DOI: 10.1039/C8EW00698A .

Second Runner-up Best Paper: Genter, Marks, Clair-Caliot, Mugume, Johnston, Bain, Julian, Evaluation of the novel substrate RUG™ for the detection of Escherichia coli in water from temperate (Zurich, Switzerland) and tropical (Bushenyi, Uganda) field sites , Environ. Sci.: Water Res. Technol. , 2019, 5 , 1082–1091, DOI: 10.1039/C9EW00138G .

Best Review Article: Okoffo, O’Brien, O’Brien, Tscharke, Thomas, Wastewater treatment plants as a source of plastics in the environment: a review of occurrence, methods for identification, quantification and fate , Environ. Sci.: Water Res. Technol. , 2019, 5 , 1908–1931, DOI: 10.1039/C9EW00428A .

Environmental Science: Nano

First Runner-up Best Paper: Janković, Plata, Engineered nanomaterials in the context of global element cycles , Environ. Sci.: Nano , 2019, 6 , 2697–2711, DOI: 10.1039/C9EN00322C .

Second Runner-up Best Paper: González-Pleiter, Tamayo-Belda, Pulido-Reyes, Amariei, Leganés, Rosal, Fernández-Piñas, Secondary nanoplastics released from a biodegradable microplastic severely impact freshwater environments , Environ. Sci.: Nano , 2019, 6 , 1382–1392, DOI: 10.1039/C8EN01427B .

Best Review Article: Lv, Christie, Zhang, Uptake, translocation, and transformation of metal-based nanoparticles in plants: recent advances and methodological challenges , Environ. Sci.: Nano , 2019, 6 , 41–59, DOI: 10.1039/C8EN00645H .

Congratulations to the authors of these papers and a hearty thanks to all of our authors. As one can clearly see from the papers listed above, environmental science is a global effort and we are thrilled to have contributions from around the world. In these challenging times, we are proud to publish research that is not only great science, but also relevant to the health of the environment and the public. Finally, we also wish to extend our thanks to our community of editors, reviewers, and readers. We look forward to another outstanding year of Environmental Science , reading the work generated not just from our offices at home, but also from back in our laboratories and the field.

Kris McNeill, Editor-in-Chief

Paige Novak, Editor-in-Chief

Peter Vikesland, Editor-in-Chief

• A. B Boehm, Risk-based water quality thresholds for coliphages in surface waters: effect of temperature and contamination aging, Environ. Sci.: Processes Impacts , 2019, 21 , 2031–2041,   10.1039/C9EM00376B .
• L. Cai, C. Liu, G. Fan, C Liu and X. Sun, Preventing viral disease by ZnONPs through directly deactivating TMV and activating plant immunity in Nicotiana benthamiana , Environ. Sci.: Nano , 2019, 6 , 3653–3669,   10.1039/C9EN00850K .
• L. W. Gassie, J. D. Englehardt, N. E. Brinkman, J. Garland and M. K. Perera, Ozone-UV net-zero water wash station for remote emergency response healthcare units: design, operation, and results, Environ. Sci.: Water Res. Technol. , 2019, 5 , 1971–1984,   10.1039/C9EW00126C .
• L. M. Hornstra, T. Rodrigues da Silva, B. Blankert, L. Heijnen, E. Beerendonk, E. R. Cornelissen and G. Medema, Monitoring the integrity of reverse osmosis membranes using novel indigenous freshwater viruses and bacteriophages, Environ. Sci.: Water Res. Technol. , 2019, 5 , 1535–1544,   10.1039/C9EW00318E .
• A. H. Hassaballah, J. Nyitrai, C. H. Hart, N. Dai and L. M. Sassoubre, A pilot-scale study of peracetic acid and ultraviolet light for wastewater disinfection, Environ. Sci.: Water Res. Technol. , 2019, 5 , 1453–1463,   10.1039/C9EW00341J .
• W. Khan, J.-Y. Nam, H. Woo, H. Ryu, S. Kim, S. K. Maeng and H.-C. Kim, A proof of concept study for wastewater reuse using bioelectrochemical processes combined with complementary post-treatment technologies, Environ. Sci.: Water Res. Technol. , 2019, 5 , 1489–1498,   10.1039/C9EW00358D .
• J. Heffron, B. McDermid and B. K. Mayer, Bacteriophage inactivation as a function of ferrous iron oxidation, Environ. Sci.: Water Res. Technol. , 2019, 5 , 1309–1317,   10.1039/C9EW00190E .
• S. Torii, T. Hashimoto, A. T. Do, H. Furumai and H. Katayama, Impact of repeated pressurization on virus removal by reverse osmosis membranes for household water treatment, Environ. Sci.: Water Res. Technol. , 2019, 5 , 910–919,   10.1039/C8EW00944A .
• J. Miao, H.-J. Jiang, Z.-W. Yang, D.-y. Shi, D. Yang, Z.-Q. Shen, J. Yin, Z.-G. Qiu, H.-R. Wang, J.-W. Li and M. Jin, Assessment of an electropositive granule media filter for concentrating viruses from large volumes of coastal water, Environ. Sci.: Water Res. Technol. , 2019, 5 , 325–333,   10.1039/C8EW00699G .
• K. L. Nelson, A. B. Boehm, R. J. Davies-Colley, M. C. Dodd, T. Kohn, K. G. Linden, Y. Liu, P. A. Maraccini, K. McNeill, W. A. Mitch, T. H. Nguyen, K. M. Parker, R. A. Rodriguez, L. M. Sassoubre, A. I. Silverman, K. R. Wigginton and R. G. Zepp, Sunlight mediated inactivation of health relevant microorganisms in water: a review of mechanisms and modeling approaches, Environ. Sci.: Processes Impacts , 2018, 20 , 1089–1122,   10.1039/C8EM00047F .

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Orthop J Sports Med
• v.10(12); 2022 Dec

The 50 Most Cited Papers Pertaining to American Football: Analysis of Studies From the Past 40 Years

Anna s. jenkins.

* Mayo Clinic Alix School of Medicine, Mayo Clinic, Scottsdale, Arizona, USA.

Michael L. Moore

Jordan r. pollock, joseph c. brinkman.

† Department of Orthopedic Surgery, Mayo Clinic, Phoenix, Arizona, USA.

Jens Verhey

Anikar chhabra, background:.

Bibliometric citation analyses have been widely used in medicine to help researchers gain foundational knowledge about a topic and identify subtopics of popular interest for further investigations.

To identify the 50 most cited research publications related to American football.

Study Design:

Cross-sectional study.

The Clarivate Analytics Web of Science database was used to generate a list of publications relating to football. Articles were filtered by the total number of citations, and the top 50 most cited articles studying the sport of football were selected for this analysis. Articles were analyzed by author, publication year, country of origin, institution affiliation, journal, article type, main research topic area, competitive level, and the level of evidence. A total of 247 articles were reviewed to reach the top 50 articles.

The most studied topic within the top 50 articles was concussion/chronic traumatic encephalopathy (n = 40). Collegiate football was the most studied level of competition (n = 25). The journal publishing the greatest number of top articles was Neurosurgery. Two institutions, the University of North Carolina at Chapel Hill and Boston University School of Medicine, produced over one-third of top 50 articles (n = 18).

Conclusion:

Our analysis indicated that most of the top 50 publications related to the sport of football focused on concussion and CTE, were observational, and were published during or after 2000. The most studied level of competition was collegiate football.

Football is America’s most popular sport, in both participation and fandom. 84 - 86 , 90 The most of any sport, football has more than 1 million high school and 40,000 college participants, and National Football League games consisted of 75 of the 100 most watched telecasts in the United States in 2021. 45 , 84 , 85 Despite its popularity, football results in more catastrophic injuries and fatalities than any other American sport. 51 Football-related injuries account for roughly 380,474 emergency department visits in youth aged less than 25 annually. 100 As awareness of football-related injuries has grown, national attention has fallen on the corresponding long-term negative impacts on player health. 40 , 55

The growing concern surrounding football-related injuries has further increased demand for research to understand injury risk factors and prevention. Topics of research relating to football are broad, ranging from performance to injury-related topics 4 , 17 , 56 , 107 to social and political issues. 38 , 101 , 103 With such a wide scope of research, it has become difficult to identify the most significant and impactful findings relating to football injuries. Bibliometric analyses provide a way to condense this ever-growing research, as articles with a greater number of citations are often considered the most influential in a field, and bibliometric citation analyses provide quantitative representation of an article’s impact. 1 , 16 , 27 , 28 , 95 Bibliometric citation analyses help researchers to focus on the most impactful scientific articles, build foundational knowledge, and identify areas for future work. They have been widely used in medicine, § medical education, 6 biomechanics, 49 ecology, 110 biotechnology, 25 and various other fields. 5 , 22 , 66

The purpose of this study was to identify the 50 most frequently cited research publications related to the sport of American football. Because of the increasing national interest and debate surrounding injuries in football and player long-term well-being, we hypothesized that the majority of publications relating to football would be in the field of medicine.

The present study was deemed minimal risk and exempt from institutional review board approval, as analysis was conducted on publicly available data. The Clarivate Analytics Web of Knowledge database was utilized to query journal articles and their respective citation metrics. A similar study design and data analysis protocol was followed as previously described in other peer-reviewed studies conducting bibliometric analyses on orthopaedic topics. 2 , 10 , 11 , 15 , 41 , 57 , 83 , 106 No citation tracking service is perfect and all-inclusive; however, the Clarivate Analytics Web of Knowledge database represents a trusted, highly extensive database that archives over 21,000 peer-reviewed journals, including 1.9 billion cited references from more than 171 million records globally. 99 Additionally, articles dating back all the way to 1900 are included in the database and its citation tracking. This database has previously received recognition for its high-quality citation links, citation accuracy, comprehensive and wide-reaching journal coverage, and consistent use by numerous previous citation analyses. 9 , 108

The Clarivate Analytics Web of Knowledge database was queried on April 14, 2022, for all article titles, abstracts, and keywords including the term “football.” No restrictions on language, journal, date, or country of origin were placed. The initial query resulted in a total of 23,573 articles, which were subsequently arranged in descending order based on the total number of citations they had accumulated. Then, the title and abstract of each article were reviewed to determine its relevance and potential inclusion into the top 50 most cited list. For inclusion, the article in question had to specifically enroll football players at any competitive level into their research study or review. Studies analyzing >1 sport were considered if football was included and was a primary focus of discussion in the paper. If inclusion of a study was in question, the full article was obtained and reviewed independently by 2 authors (J.R.P. and M.L.M.) to decide on inclusion or exclusion. If the authors could not agree, the senior author (A.C.) determined whether or not the article was included. Articles with only a peripheral mention of football in their methods or discussion were excluded. Additionally, articles that studied football (soccer) were excluded.

A total of 247 articles were reviewed to reach the 50 most cited studies that met the inclusion criteria outlined above. The full text for the 50 included studies was obtained and reviewed in order to obtain the following pieces of information: first and last author name, publication year, country of origin (determined by the affiliation of the first author), institutional affiliation (of both the first author and last author), journal name, study type, primary research topic area (concussion/chronic traumatic encephalopathy [CTE], physiology, biomechanics, nutrition, microbiology, training and testing, sports medicine, performance analysis, sports psychology, coaching, and social science), level of competition (high school, college, and/or professional), and level of evidence. Articles were designated as a review article if they incorporated a systematic approach to reviewing the literature or if a meta-analysis was performed. If an article incorporated the results and discussion of previously published literature, but a systematic approach to reviewing the literature was not outlined, the article was classified as expert opinion. Additionally, an article was categorized as being either medical or nonmedical based on whether the focus of the study involved the treatment, assessment, rehabilitation, classification, or diagnosis of medical pathology. Epidemiologic studies that assessed injury or medical condition prevalence or incidence were included. If an article did employ ≥1 of the above focuses in its design, it was categorized as nonmedical (eg, biomechanics, sports performance, exercise testing, etc). The level of evidence was assigned to each article based on the guidelines published by the Centre for Evidence-Based Medicine. 43

Once the top 50 most cited articles were identified and the above information was extracted for each study, summary statistics were calculated. These calculations included the total number of citations and the total number of publications accumulated each year and the total number of articles representing a specific study type, level of evidence, and field of research. Additionally, the most cited and most represented first/last authors, countries of origin, publishing journal, and academic institutions were calculated. The citation density of each article was also calculated by taking the total number of citations divided by the number of years since publication.

The 50 most cited publications related to football are listed in Appendix Table A1 , along with their rank, number of citations, and citation density. The number of citations per article ranged from 213 to 1434, and 7 articles were cited over 1000 times. The mean number of citations per articles was 419, and the median was 329. The average citation density was 25.8 (range, 10.7-102.4).

Descriptive characteristics of the top 50 articles are shown in Table 1 . Of the top 50 articles relating to football, 46 related to medicine, with 40 articles focusing on concussion or CTE and 6 on sports medicine. The next most common topic was microbiology (n = 2), follwed by sports psychology (n = 1), and training and testing (n = 1). All articles were published in the United States. Over half of the top 50 most cited articles were cohort studies (n = 26), and 11 were descriptive studies. Most of the top 50 articles relating to football focused on 1 specific level of competition, with 16 publications focusing on college football, 14 on professional, and 10 on high school. One article studied both high school and professional football, 4 studied high school and college, and 5 studied all 3 levels. College was the most well-studied level of competition, with half of the top 50 articles including college football in their analysis (n = 25).

Descriptive Characteristics of Top 50 Most Cited Articles Relating to Football

The top 50 articles were all published between 1976 and 2017 ( Figure 1 ). When analyzing which years produced the top-cited publications, we included ranking by citation density as well as number of citations to address the factor of time to accrue citations. The top 5 articles ranked by citation density were published between 2007 and 2013, whereas the top 5 articles ranked by number or citation were published between 1976 and 2017. Of the top 50 articles, 19 were published between 2003 and 2007, and 39 of the top 50 were published in 2000 or later. The number of citations each of the top 50 articles received per year ranged from 0 (in 1981) to 2301 (in 2019) ( Figure 2 ).

Number of top 50 most cited articles relating to American football published by year.

Total number of citations generated by the top 50 most cited articles relating to American football each year.

The majority of the 50 most cited articles had an evidence level of either 2 (n = 11), 3 (n = 18), or 4 (n = 19) ( Figure 3 ). Level 1 (n = 1) and level 5 (n = 1) research comprised less than 4% of top publications.

The level of evidence of the top 50 most cited articles relating to American football.

When assessing author impact, we found that 14 authors published ≥1 of the 50 most cited articles relating to football. Table 2 further breaks down author impact, listing each of these 14 authors’ total number of publications, first author publications, last author publications, total number of citations, and average number of citations per publication. The most prolific author within our analysis was Kevin M. Guskiewicz, with the greatest number of total citations (4113) and publications (n = 6). The affiliated institutions for the first author and last author of the top 50 articles are presented in Table 3 . The 2 institutions publishing the greatest number of top 50 articles were the University of North Carolina at Chapel Hill and Boston University School of Medicine, each with 9 publications.

Descriptive Data of Authors Publishing 2 or More of the Top 50 Most Cited Articles Relating to American Football

Institutions of First and Last Authors of Top 50 Most Cited Articles Relating to American Football

Regarding publication source, the top 50 most cited articles were published in 20 different journals ( Table 4 ). The journal publishing the greatest proportion of top 50 articles was Neurosurgery (n = 9). The next 3 journals with the most publications within the top 50 articles were the Journal of Athletic Training (n = 6), Journal of the American Medical Association (n = 6), and American Journal of Sports Medicine (n = 5). All of the articles published by Neurosurgery and the Journal of the American Medical Association focused on CTE/concussion; half published by the Journal of Athletic Training focused on CTE/concussion. The majority of articles (n = 28) were not open access journals, compared with 22 that were open access.

The Publishing Journals of the 50 Most Highly Cited Articles Relating to American Football

As hypothesized, the majority of highly cited publications on American football were medicine related and focused on injuries, although we did not hypothesize that the majority of studied injuries would pertain to concussion and CTE. The major findings of our research showed that of the top 50 publications, 46 (92%) were in the field of medicine, with 40 (80%) studying concussion or CTE. The predominance of concussion and CTE research reflects increasing awareness and concern surrounding head injury in football. 39 , 69 A review of the publications included in our analysis may help physicians, physical therapists, athletic trainers, and coaches who work with football players to establish foundational knowledge on injury prevention recommendations and treatment guidelines.

The top-cited article in our analysis had 1434 citations, studied concussion and CTE, and was published in 2009. 76 In comparison, a recent bibliometric analysis of concussion-related publications found that the top article was cited 3204 times and was published in 2022. 102 Additionally, we found a mean of 419 citations per article, while the mean citation frequency of top concussion-related publications was reportedly 1033. 18 We postulate that articles in our analysis accrued fewer citations than top concussion-related publications because of a narrower focus on concussions related to football.

Our finding that all top 50 articles were published within the United States is expected given football’s predominantly American domain and is consistent with findings previously reported by Sharma and Lawrence 102 regarding popular concussion literature. As with other bibliometric analyses relating to sports medicine, the majority of our studies were observational, with 48 (96%) of 50 publications having level 2, 3, or 4 evidence. 47

Collegiate football was the most studied level of competition among the top football-related publications. This is somewhat unexpected, given the predominance of competitive football players at the high school level compared with the collegiate level (1 million and 40,000, respectively). 84 , 85 Our findings may suggest a study bias toward higher-level players and indicate the need for additional research on youth and high school football, especially considering differences in the neural development of younger players, which likely alters injury prevention strategies and treatment practices. The discrepancy between participation rates and the focus of top publications may also reflect differences in funding, with higher-level football attracting more funding for research. Alternatively, it is possible that higher-level players are more studied because of logistical advantages of injury surveillance. Additionally, concussion and CTE are cumulative injuries that become more deleterious as frequency of injury occurs, often presenting later in one’s career (or even postmortem, when CTE cases are confirmed), and therefore more easily studied in older players.

The present analysis revealed that 19 (38%) of the top 50 most cited articles were published between 2003 and 2007, and the top 5 articles by citation density were each published in or after 2007. More recent works have had greater influence in football-related research based on citation density, as public awareness of football-related injuries aligns with an exponential increase in concussion-related research between 2000 and 2020. 102 There has been a shift of national attention on the risks of brain injury specifically in the sport of football; although participation in football has always been associated with an increased risk of concussion, awareness of football-related head injury rapidly increased in the 21st century, a phenomenon that has been termed “the first concussion crisis.” 40 The publications identified in our analysis may have contributed to increased national awareness of football-related head injury; they may also have been a product of media attention on football injury. Our finding that the top 5 articles by citation density were published between 2007 and 2017 may reflect the increase in national awareness of and subsequent concern over football-related injuries that occurred in the early 2000s. 30 , 39 , 40

Kevin M. Guskiewicz from the University of North Carolina at Chapel Hill and Michael McCrea from the Medical College of Wisconsin were the top 2 authors in the football-related injury literature. 33 , 34 - 36 , 37 , 39 , 71 – 75 At the institutional level, the University of North Carolina at Chapel Hill and Boston University School of Medicine were the 2 most proliferative institutions in football injury research. Both institutions had >1 primary author producing top articles, and together these 2 institutions contributed over one-third of the top 50 publications. As bibliometric analyses provide insight into which authors and institutions are most prominent in a particular field, our findings suggest the dominance of the University of North Carolina at Chapel Hill and Boston University School of Medicine in football research. 28 , 29 , 60 , 61 It is also important to consider, however, that most of the top-cited publications studied neuro-related injuries and may have come from investigators whose work specialized in this area. 33 – 37 , 71 – 75 As such, in building upon their prior research, these investigators may often cite their prior publications and publications from their own institution. Additionally, certain institutions may have more research funding and larger departments, particularly if orthopaedic/football research is a priority of the institution.

Evaluating journal impact on football-related research, Neurosurgery was the journal with the most publications in the top 50, followed by the Journal of Athletic Training and Journal of the American Medical Association. The articles published by these journals predominantly focused on CTE and concussion, the most highly studied topic. As citation analysis has been used to evaluate journal impact, students and practitioners seeking to remain at the cutting edge of football injury literature may focus their attention on these journals. 28 , 29 Furthermore, journals that published multiple top publications were exclusively journals with a focus on medical topics, an unsurprising finding given that the overwhelming majority (92%) of published articles in our analysis were medicine related. While the majority of articles were not open access, a significant portion (44%) were, likely lowering barriers to readership and subsequent citation of their publications.

While our analysis indicates areas that are particularly well studied relating to football, it also highlights a few gaps in the current literature. One gap is in the study of injuries unrelated to CTE and head injury: below-the-head injuries occur frequently and, as with concussion and CTE, can cause significant and long-term disability to players. Research relating to the prevention and treatment of these injuries merits attention. Additionally, future research may focus on innovations in faster and safer injury rehabilitation.

Limitations

The top 50 publications were selected by number of accrued citations, a metric that may be influenced by a variety of factors, including research funding disparities by competition level, positive outcome bias, time since publication date, institutional prestige, and dissemination bias. Therefore, while citation frequency is an indicator of article importance, it should not be used as the sole determinant of study quality or study influence on injury protocols and clinical practice. Citation density accounts for time elapsed since study publication date and was included in our analysis to assess article citation frequency equitably across time. Another limitation of our work is the exclusion of the newest publications, a shortcoming of all bibliometric analyses, as newer publications are not allowed adequate time to accrue citations. Often, studies reach prominence several years after their initial publication date. 28 A final limitation is our use of only 1 database. While the database utilized in the present study is commonly employed in bibliometric analyses, other databases may yield slightly different findings. 2 , 10 , 11 , 15 , 41 , 57 , 83 Other commonly utilized databases include PubMed, Scopus, and Google Scholar. 9 , 26 , 52

Our analysis indicated that most publications related to American football focused on concussion and CTE, were observational, and were published during or after 2000. The most studied level of competition was college. Our list of the top 50 most cited studies provides researchers, medical students, residents, and fellows with a foundational list of the most important and influential academic contributions to the literature on American football.

Appendix Table A1

The Top 50 Most Cited Articles Relating to American Football

§ References 3 , 7 , 8 , 13 , 27 , 32 , 44 , 53 , 54 , 59 , 63 , 78 , 81 , 82 .

Final revision submitted August 28, 2022; accepted September 15, 2022.

One or more of the authors has declared the following potential conflict of interest or source of funding: A.C. has received education payments from Arthrex and consulting fees from Zimmer Biomet. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Ethical approval was not sought for the present study.

• Download PDF
• Share X Facebook Email LinkedIn
• Permissions

Clinical Reasoning of a Generative Artificial Intelligence Model Compared With Physicians

• 1 Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
• 2 Department of Medicine, Massachusetts General Hospital, Boston
• 3 Department of Pulmonary and Critical Care, Brigham and Women’s Hospital, Boston, Massachusetts

Large language models (LLMs) have shown promise in clinical reasoning, but their ability to synthesize clinical encounter data into problem representations remains unexplored. 1 - 3 We compared an LLM’s reasoning abilities against human performance using standards developed for physicians.

Read More About

Cabral S , Restrepo D , Kanjee Z, et al. Clinical Reasoning of a Generative Artificial Intelligence Model Compared With Physicians. JAMA Intern Med. Published online April 01, 2024. doi:10.1001/jamainternmed.2024.0295

Manage citations:

© 2024

Artificial Intelligence Resource Center

Best of JAMA Network 2022

Browse and subscribe to JAMA Network podcasts!

Others Also Liked

Select your interests.

Customize your JAMA Network experience by selecting one or more topics from the list below.

• Academic Medicine
• Acid Base, Electrolytes, Fluids
• Allergy and Clinical Immunology
• American Indian or Alaska Natives
• Anesthesiology
• Anticoagulation
• Art and Images in Psychiatry
• Artificial Intelligence
• Assisted Reproduction
• Bleeding and Transfusion
• Caring for the Critically Ill Patient
• Challenges in Clinical Electrocardiography
• Climate and Health
• Climate Change
• Clinical Challenge
• Clinical Decision Support
• Clinical Implications of Basic Neuroscience
• Clinical Pharmacy and Pharmacology
• Complementary and Alternative Medicine
• Consensus Statements
• Coronavirus (COVID-19)
• Critical Care Medicine
• Cultural Competency
• Dental Medicine
• Dermatology
• Diabetes and Endocrinology
• Diagnostic Test Interpretation
• Drug Development
• Electronic Health Records
• Emergency Medicine
• End of Life, Hospice, Palliative Care
• Environmental Health
• Equity, Diversity, and Inclusion
• Facial Plastic Surgery
• Gastroenterology and Hepatology
• Genetics and Genomics
• Genomics and Precision Health
• Global Health
• Guide to Statistics and Methods
• Hair Disorders
• Health Care Delivery Models
• Health Care Economics, Insurance, Payment
• Health Care Quality
• Health Care Reform
• Health Care Safety
• Health Care Workforce
• Health Disparities
• Health Inequities
• Health Policy
• Health Systems Science
• History of Medicine
• Hypertension
• Images in Neurology
• Implementation Science
• Infectious Diseases
• Innovations in Health Care Delivery
• JAMA Infographic
• Law and Medicine
• Leading Change
• Less is More
• LGBTQIA Medicine
• Lifestyle Behaviors
• Medical Coding
• Medical Devices and Equipment
• Medical Education
• Medical Education and Training
• Medical Journals and Publishing
• Mobile Health and Telemedicine
• Narrative Medicine
• Neuroscience and Psychiatry
• Notable Notes
• Nutrition, Obesity, Exercise
• Obstetrics and Gynecology
• Occupational Health
• Ophthalmology
• Orthopedics
• Otolaryngology
• Pain Medicine
• Palliative Care
• Pathology and Laboratory Medicine
• Patient Care
• Patient Information
• Performance Improvement
• Performance Measures
• Perioperative Care and Consultation
• Pharmacoeconomics
• Pharmacoepidemiology
• Pharmacogenetics
• Pharmacy and Clinical Pharmacology
• Physical Medicine and Rehabilitation
• Physical Therapy
• Physician Leadership
• Population Health
• Primary Care
• Professional Well-being
• Professionalism
• Psychiatry and Behavioral Health
• Public Health
• Pulmonary Medicine
• Regulatory Agencies
• Reproductive Health
• Research, Methods, Statistics
• Resuscitation
• Rheumatology
• Risk Management
• Scientific Discovery and the Future of Medicine
• Shared Decision Making and Communication
• Sleep Medicine
• Sports Medicine
• Stem Cell Transplantation
• Substance Use and Addiction Medicine
• Surgical Innovation
• Surgical Pearls
• Teachable Moment
• Technology and Finance
• The Art of JAMA
• The Arts and Medicine
• The Rational Clinical Examination
• Tobacco and e-Cigarettes
• Translational Medicine
• Trauma and Injury
• Treatment Adherence
• Ultrasonography
• Users' Guide to the Medical Literature
• Vaccination
• Venous Thromboembolism
• Veterans Health
• Women's Health
• Workflow and Process
• Wound Care, Infection, Healing
• Register for email alerts with links to free full-text articles
• Access PDFs of free articles
• Manage your interests
• Save searches and receive search alerts

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts

Collection  29 March 2022

2021 Top 25 Chemistry and Materials Sciences Articles

We are pleased to share with you the 25 most downloaded  Nature Communications  articles* in chemistry and materials sciences published in 2021. Featuring authors from around the world, these papers highlight valuable research from an international community.

Browse all Top 25 subject area collections  here .

*Data obtained from SN Insights (based on Digital Science's Dimensions) and normalised to account for articles published later in the year.

Research highlights

Mechanochemical synthesis of magnesium-based carbon nucleophiles in air and their use in organic synthesis

Grignard reagents have widespread utility in organic chemistry, but their preparation is limited by several drawbacks, such as the use of dry organic solvents and long reaction times. Here, the authors report a general mechanochemical synthesis of Grignard reagents in paste form in air, using a ball milling technique.

• Rina Takahashi

Programmable microbial ink for 3D printing of living materials produced from genetically engineered protein nanofibers

Living cells can precisely assemble to build 3D functional architectures. Here the authors produce an extrudable microbial ink entirely from the engineered cells, which can be further programmed to 3D print functional living materials.

• Anna M. Duraj-Thatte
• Avinash Manjula-Basavanna
• Neel S. Joshi

A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems

Lipid nanoparticle delivery of mRNA vaccines has become of particular importance, however, mRNA stability is a major concern. Here, the authors report on a study of lipid impurity mRNA interactions using reverse phase ion pair HPLC to identify reactions which render the mRNA untranslatable, reducing vaccine efficiency.

• Meredith Packer
• Dipendra Gyawali

Understanding Li-based battery materials via electrochemical impedance spectroscopy

Electrochemical impedance spectroscopy is a key technique for understanding Li-based battery processes. Here, the authors discuss the current state of the art, advantages and challenges of this technique, also giving an outlook for future developments.

• Miran Gaberšček

A general strategy for C(sp 3 )–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor

When carbon-based units are functionalized in photoredox catalysis, electrophilic coupling partners are often used, such that the polarities of the two fragments are appropriately matched. Here the authors show a generalized methodology to instead use nucleophilic coupling partners, which are cheaper and often simpler, via successive hydrogen atom transfer and oxidative radical-polar crossover.

• Isabelle Nathalie-Marie Leibler
• Makeda A. Tekle-Smith
• Abigail G. Doyle

Identifying molecules as biosignatures with assembly theory and mass spectrometry

The search for life in the universe is difficult due to issues with defining signatures of living systems. Here, the authors present an approach based on the molecular assembly number and tandem mass spectrometry that allows identification of molecules produced by biological systems, and use it to identify biosignatures from a range of samples, including ones from outer space.

• Stuart M. Marshall
• Cole Mathis
• Leroy Cronin

Tempering of cocoa butter and chocolate using minor lipidic components

In chocolate production, a complicated tempering process is used to guide the crystallization of cocoa butter towards its most desirable polymorph, which gives the chocolate proper melting behavior, gloss, and snap—hallmarks of good quality chocolate. Here, the authors find that simply adding a specific phospholipid also directs crystallization towards this polymorph, producing chocolate with comparable microstructure and properties to tempered chocolate.

• Saeed M. Ghazani
• Alejandro G. Marangoni

Production of high-energy Li-ion batteries comprising silicon-containing anodes and insertion-type cathodes

Large-scale manufacturing of high-energy Li-ion cells is of paramount importance for developing efficient rechargeable battery systems. Here, the authors report in-depth discussions and evaluations on the use of silicon-containing anodes together with insertion-based cathodes.

• Gebrekidan Gebresilassie Eshetu
• Egbert Figgemeier

Proliferating coacervate droplets as the missing link between chemistry and biology in the origins of life

Coacervate droplets (CDs) are a model for protocells formed by liquid-liquid phase separation (LLPS), but protocell models able to proliferate remain undeveloped. Here, the authors report a proliferating peptide-based CD using synthesised amino acid thioesters as monomers, which could concentrate RNA and lipids, enabling RNA to protect the droplet from dissolution by lipids.

• Muneyuki Matsuo
• Kensuke Kurihara

Nickel-catalyzed electrochemical carboxylation of unactivated aryl and alkyl halides with CO 2

Electrochemistry is a promising approach to make existing chemical protocols milder, but many simple transformations of feedstocks are still out of reach. Here, the authors transform unactivated aryl and alkyl (pseudo)halides into carboxylic acids, via nickel catalysis and electricity, using atmospheric CO 2 as the carbon source.

• Guo-Quan Sun

Gene editing enables rapid engineering of complex antibiotic assembly lines

Engineering biosynthetic assembly lines is a powerful path to new natural products but is challenging with current methods. Here the authors use CRISPR-Cas9 to exchange subdomains within NRPS to alter substrate selectivity.

• Wei Li Thong
• Yingxin Zhang
• Jason Micklefield

Electrochemical ammonia synthesis via nitrate reduction on Fe single atom catalyst

Developing green and delocalized routes for ammonia synthesis is highly important but still very challenging. Here the authors report an efficient ammonia synthesis process via nitrate reduction to ammonia on Fe single atom catalyst.

• Mohammadreza Karamad
• Haotian Wang

Coordination environment dependent selectivity of single-site-Cu enriched crystalline porous catalysts in CO 2 reduction to CH 4

Crystalline porous catalysts with single Cu sites are dedicated to exploring the dependence of CO 2 electroreduction selectivity on the coordination environment of catalytic sites. The conductive MOF Cu-DBC with oxygen-coordinated Cu sites shows a high Faradaic efficiency ~80% of CO 2 -to-CH 4 .

• Long-Zhang Dong
• Ya-Qian Lan

6 nm super-resolution optical transmission and scattering spectroscopic imaging of carbon nanotubes using a nanometer-scale white light source

The authors present a super-resolution hyperspectral imaging technique using a nanoscale white light source generated by superfocusing light from a tungsten-halogen lamp. They achieve 6 nm resolution, measuring longitudinal and transverse optical electronic transitions in single-walled carbon nanotubes.

Electrochemical C–N bond activation for deaminative reductive coupling of Katritzky salts

Electrochemical transformations use electrons and electron holes instead of chemical oxidants and reductants as reagents. Here, the authors report an electrochemical reductive deaminative cross-coupling of Katrizky salts with various radical acceptors, including examples of fluoroalkenylation, alkynylation and thiolation.

• Xiangzhang Tao

Ultra-thin self-healing vitrimer coatings for durable hydrophobicity

By now a plethora of ultrathin hydrophobic coatings are available but their durability are not well developed. Here, the authors present a thin, durable and fluorine-free PDMS-based vitrimer coating that implements many desirable aspects like energy efficiency, durability and sustainability.

• Jingcheng Ma
• Laura E. Porath
• Christopher M. Evans

A saccharide-based binder for efficient polysulfide regulations in Li-S batteries

The long-term cycling of Li-S batteries depends on the polysulfides shuttling regulation. Here, the authors present a saccharide-based binder system to control the polysulfides migration and improve the cycle life of a Li-S pouch cell.

• Yingyi Huang
• Mahdokht Shaibani
• Mainak Majumder

Sustained enzymatic activity and flow in crowded protein droplets

Living cells can harvest environmental energy to drive chemical processes. Here the authors design a minimal artificial system that achieves steady states at similar metabolic densities to microorganisms.

• Andrea Testa
• Mirco Dindo
• Paola Laurino

Freezing of few nanometers water droplets

Ice nucleation in confined geometries is a ubiquitous phenomenon, but difficult to characterize. Here the authors investigate experimentally the freezing of water nanodroplets surrounded by octane in nanopores down to 2 nm, and demonstrate that the soft curved oil-water interface suppresses heterogeneous ice nucleation, which occurs at a lower temperature than homogenous bulk nucleation.

• Alireza Hakimian
• Mohammadjavad Mohebinia
• Hadi Ghasemi

Transition metal-doped Ni-rich layered cathode materials for durable Li-ion batteries

Long-term efficient cycling stability is of paramount importance for the development of high-energy Li-ion batteries. Here, the authors investigate the effect of transition metal dopants on the electrochemical, morphological, and structural properties of Ni-rich cathode active materials.

• H. Hohyun Sun
• Un-Hyuck Kim
• Yang-Kook Sun

Divergent functionalization of aldehydes photocatalyzed by neutral eosin Y with sulfone reagents

Acyl radicals represent a reactive species that allow for aldehyde subunits to be nucleophilic instead of their typical electrophilic behavior; however, these species are difficult to access in mild conditions. Here the authors show a method to generate acyl radicals using only an organic photocatalyst and light, and these species are shown as competent nucleophiles in a variety of couplings.

• Jianming Yan

Engineering single-atomic ruthenium catalytic sites on defective nickel-iron layered double hydroxide for overall water splitting

Rational design of single atom catalyst is critical for efficient sustainable energy conversion. Single-atomic-site ruthenium stabilized on defective nickel-iron layered double hydroxide nanosheets achieve superior HER and OER performance in alkaline media.

• Panlong Zhai
• Mingyue Xia
• Jungang Hou

Artificial intelligence-enhanced quantum chemical method with broad applicability

Artificial intelligence is combined with quantum mechanics to break the limitations of traditional methods and create a new general-purpose method for computational chemistry simulations with high accuracy, speed and transferability.

• Peikun Zheng
• Roman Zubatyuk
• Pavlo O. Dral

Controlled self-assembly of plant proteins into high-performance multifunctional nanostructured films

Green use of plant derived proteins in functional materials has been limited by inefficient methods to control micro and nanoscale structure. Here, the authors use nanoscale assembly of water-insoluble plant proteins to make meter scale films with comparable properties to conventional plastics.

• Ayaka Kamada
• Marc Rodriguez-Garcia
• Tuomas P. J. Knowles

Moving beyond bimetallic-alloy to single-atom dimer atomic-interface for all-pH hydrogen evolution

While single, dispersed atoms enable efficient atomic utilization, controllably preparing single-atom dimers remains challenging. Here, authors prepare nickel-cobalt single-atom dimers as high-performance pH-universal H 2 evolution electrocatalysts.

• Ashwani Kumar
• Viet Q. Bui
• Hyoyoung Lee

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

This paper is in the following e-collection/theme issue:

Published on 18.4.2024 in Vol 26 (2024)

The Alzheimer’s Knowledge Base: A Knowledge Graph for Alzheimer Disease Research

Authors of this article:

Original Paper

• Joseph D Romano 1, 2, 3 , MA, MPhil, PhD   ; 
• Van Truong 1, 4, 5 , MS   ; 
• Rachit Kumar 1, 4, 5, 6 , BS   ; 
• Mythreye Venkatesan 7 , BE, MS   ; 
• Britney E Graham 7 , PhD   ; 
• Yun Hao 1, 4 , PhD   ; 
• Nick Matsumoto 7 , BA   ; 
• Xi Li 7 , MS   ; 
• Zhiping Wang 7 , MS, PhD   ; 
• Marylyn D Ritchie 1, 3, 5 , PhD   ; 
• Li Shen 1, 3 , PhD   ; 
• Jason H Moore 7 , PhD  

1 Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

2 Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

3 Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

4 Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

5 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

6 Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

7 Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States

Corresponding Author:

Joseph D Romano, MA, MPhil, PhD

Institute for Biomedical Informatics

Perelman School of Medicine

University of Pennsylvania

403 Blockley Hall

423 Guardian Drive

Philadelphia, PA, 19104

United States

Phone: 1 2155735571

Email: [email protected]

Background: As global populations age and become susceptible to neurodegenerative illnesses, new therapies for Alzheimer disease (AD) are urgently needed. Existing data resources for drug discovery and repurposing fail to capture relationships central to the disease’s etiology and response to drugs.

Objective: We designed the Alzheimer’s Knowledge Base (AlzKB) to alleviate this need by providing a comprehensive knowledge representation of AD etiology and candidate therapeutics.

Methods: We designed the AlzKB as a large, heterogeneous graph knowledge base assembled using 22 diverse external data sources describing biological and pharmaceutical entities at different levels of organization (eg, chemicals, genes, anatomy, and diseases). AlzKB uses a Web Ontology Language 2 ontology to enforce semantic consistency and allow for ontological inference. We provide a public version of AlzKB and allow users to run and modify local versions of the knowledge base.

Results: AlzKB is freely available on the web and currently contains 118,902 entities with 1,309,527 relationships between those entities. To demonstrate its value, we used graph data science and machine learning to (1) propose new therapeutic targets based on similarities of AD to Parkinson disease and (2) repurpose existing drugs that may treat AD. For each use case, AlzKB recovers known therapeutic associations while proposing biologically plausible new ones.

Conclusions: AlzKB is a new, publicly available knowledge resource that enables researchers to discover complex translational associations for AD drug discovery. Through 2 use cases, we show that it is a valuable tool for proposing novel therapeutic hypotheses based on public biomedical knowledge.

Introduction

Alzheimer disease (AD) is a progressive, neurodegenerative disease affecting an estimated 6.5 million Americans aged ≥65 years and represents a significant clinical, economic, and emotional burden worldwide [ 1 ]. AD is often cited as one of the greatest health care problems of the 21st century, particularly in high-income nations with an increasing proportion of older adults. Despite its societal impact, effective pharmaceutical treatments for AD remain notoriously elusive. The US Food and Drug Administration has approved 5 drugs for the treatment of AD, 4 of which (donepezil, rivastigmine, galantamine, and memantine) only temporarily treat symptoms but do not alter the overall progression of the disease [ 2 ], whereas the fifth (aducanumab) is highly controversial in terms of evidence of effectiveness and its safety profile [ 3 ]. AD researchers have prioritized the discovery and approval of new therapies for the disease both in terms of newly discovered compounds and by repurposing drugs that are already approved to treat other (non-AD) human diseases.

AD is associated with substantial changes in pathology, including the presence of neuritic plaques associated with the amyloid-β protein, extracellular deposition of amyloid-β, and neurofibrillary tangles. Previous research has shown that these neuropathological changes begin to occur years before clinical symptoms are apparent [ 4 , 5 ]. Despite decades of research, why this pathology begins to develop remains largely unknown [ 6 ]. Current consensus is that AD risk is multifactorial. The most well-established risk factors include age; family history; and certain genetic factors, especially the presence of the σ4 allele of the apolipoprotein E gene, which is involved in fat metabolism and cholesterol transport. However, the exact mechanism through which these factors—including APOE -σ4 presence—cause or contribute to AD risk is unknown [ 7 ].

Of the many techniques used in AD therapeutics research, there is a wealth of computer-aided approaches that leverage recent advances in bioinformatics, epidemiology, artificial intelligence (AI), and machine learning (ML). For example, Rodriguez et al [ 8 ] developed an ML framework to assess gene lists constructed by differential gene expression data in response to drug treatment to determine whether those drugs would be candidates for repurposing in AD. Tsuji et al [ 9 ] used an autoencoder neural network to perform dimensionality reduction of a high-density protein interaction network to identify new possible drug targets and then found drugs associated with those targets. Genome-wide association studies have long been used for the identification of genes that confer AD risk, particularly for rare genes or genes with small (but statistically significant) contributions to disease risk [ 10 ].

In this paper, we describe the design and deployment of a major new knowledge resource for computational AD research—named The Alzheimer’s Knowledge Base (AlzKB) [ 11 ]—with a particular focus on drug discovery and drug repurposing. The overall structure and contents of AlzKB are summarized in Figure 1 . At its core, AlzKB consists of a large, heterogeneous graph database describing entities related to AD at multiple levels of biological organization, with rich semantic relationships describing how those entities are linked to one another. To demonstrate its value, we present two data-driven analyses involving ML on AlzKB’s knowledge graph: (1) predicting Parkinson disease (PD) genes that may also be associated with AD and (2) generating and explaining drug repurposing hypotheses for treating AD, both of which replicate existing knowledge while proposing entirely novel directions for future experimental validation. AlzKB is free, open source, and publicly available [ 11 ] and consists entirely of publicly sourced knowledge integrated from 22 diverse web-based biomedical databases. We hypothesized that the relationships and entities in AlzKB contain valuable knowledge that cannot be effectively captured in existing data resources, with the additional advantage of improving the explainability of new predictions.

Existing Graph-Based Approaches to AD Research

Due to the increased popularity and success of analyses using integrated knowledge, previous efforts have used knowledge graphs in AD research for a variety of purposes, including drug repurposing [ 12 - 14 ] and gene identification [ 15 ] and as general informational resources [ 16 ]. Similar to AlzKB, these bodies of work draw from a variety of sources to construct the underlying knowledge graphs, including scientific literature and formally structured biomedical databases. Some, including the Alzheimer Disease Knowledge Graph [ 14 ] and the Heterogeneous network-based data set for AD [ 16 ], have been released as publicly accessible resources similar to AlzKB. Other studies have used existing resources not specifically intended for AD research (such as the Semantic MEDLINE Database [ 13 ]) to answer questions related to AD. To our knowledge, AlzKB is the largest graph-based knowledge representation that focuses solely on AD and draws from the greatest number of source databases. For comparison, the next largest AD-specific knowledge graph that we are aware of is AD-KG, which contains 30,729 nodes and 398,544 edges (compared to AlzKB’s 118,902 nodes and 1,309,527 edges). Our emphasis on merging similar nodes or edges and cleaning the graph structure using an underlying biomedical ontology reduces the amount of noise that tends to be associated with many different node or edge types in a single graph, enabling more robust inference about relationships in AD, especially when used with emerging graph ML algorithms. Furthermore, AlzKB offers a public, web interface that allows for easy access and application to new research questions, whereas existing resources have either restricted access or are entirely unavailable for reuse. Given the challenge of identifying new or repurposed drugs for etiologically complex diseases such as AD, AlzKB represents a major step forward by improving both quantitatively and structurally on existing resources.

AlzKB Ontology

Graph databases are renowned for their flexibility in representing data that do not conform to a rigid, tabular structure, but this comes at the expense of implicitly enforcing consistency and semantic standardization [ 17 ]. To mitigate this issue, we designed a Web Ontology Language (OWL) 2 ontology—describing the types of entities relevant to AD and treatment of AD, as well as the types of relationships that link those entities—that serves as a template for nodes and edges in the knowledge graph. Ontologies (including OWL 2 ontologies) are formal representations of knowledge that are frequently used in biomedicine to computationally structure, retrieve, and make inferences about knowledge within a domain of interest [ 18 ]. Briefly, as many of the components of a graph database have a 1-to-1 correspondence with components of an OWL 2 ontology (eg, OWL 2 classes are equivalent to graph database node labels, and OWL 2 object properties are equivalent to edge types in a graph database), it is possible to populate the ontology using biomedical knowledge and translate the contents of the populated ontology into an equivalent graph database. Therefore, enforcing consistency in the ontology becomes equivalent to enforcing consistency in the graph database.

We constructed the ontology manually using the Protégé ontology editor (version 5.5.0; Stanford Center for Biomedical Informatics Research) [ 19 ] following an iterative process guided by expert domain knowledge. First, we prototyped a class hierarchy containing the types of nodes (eg, gene, disease, pathway, and drug) desired in the knowledge base. We then annotated these classes with data properties (eg, drugs can be assigned a property value corresponding to molecular weight) and object properties (relationship types that link 2 entities, such as “drug treats disease”). A thorough description of the components of OWL 2 ontologies is provided by Hitzler et al [ 20 ]. Finally, we placed restrictions on the ontology to reflect biology and clinical practice. For example, we specified restrictions stating that all pathways must contain one or more genes or that all drugs in the knowledge base must have a valid DrugBank ID. We repeated these steps several times, making revisions on previous iterations until several domain experts agreed that the semantic contents of the ontology were consistent with current AD knowledge and systems biology processes involved in AD etiology. After collecting the data sources used to populate the ontology (see the following section), we included additional data properties corresponding to identifiers in those source databases, enabling data provenance and facilitating both interoperability and validation. The final ontology structure consists of entity types involved in AD etiology (modeled as OWL 2 classes), types of semantic relationships that can link those entity types (modeled as OWL 2 object properties), and properties that can be annotated onto entities of specific types (modeled as OWL 2 data properties). Both before and after populating the ontology with individuals (see the Implementing AlzKB section), we validated its contents and structure by running FaCT++—an ontology inference engine that identifies errors by evaluating all assertions in the ontology against the ontology’s class or property hierarchy and other restrictions [ 21 ].

Collecting and Assembling Third-Party Data Sources

Using the AlzKB ontology’s class hierarchy as a starting point, we determined a set of the most important entity types to include in the first release of the knowledge base. For example, we prioritized inclusion of entities representing diseases (specifically AD and its various subtypes), genes, and drugs, among others. Similarly, we identified important relationship types (eg, “DRUG_BINDS_GENE” or “GENE_ASSOCIATED_WITH_DISEASE”) to include in the knowledge base. For each of these entity and relationship types, we identified a third-party, public data source that would serve as a collection of “ground truth knowledge” for that entity or relationship type. In the assembled knowledge base, there is roughly a 1-to-1 correspondence between a data record in the original “ground truth” data source and its corresponding entity or relationship in AlzKB, with some important exceptions. For example, we made the decision to only include neurological diseases in AlzKB rather than all diseases described in the “ground truth” data source (in this case, the Disease Ontology). We also identified instances in which properties from additional data sources could be used to augment the “ground truth” entities. For example, while DrugBank is used to specify the drugs described in AlzKB, we also used fields from Distributed Structure-Searchable Toxicity and PubChem to augment the properties annotated onto drugs (such as molecular weight, chemical fingerprint, and synonyms).

Implementing AlzKB

We populated the ontology by sequentially carrying out the following steps:

• Import distinct entities from each data source corresponding to the corresponding ontology class and define those entities as ontology individuals (ie, instances of that class). For example, the drug memantine is defined as an instance of the ontology class Drug.
• Populate data properties for all instances of each ontology class using data from relevant sources. For example, memantine is annotated with the Chemical Abstracts Service Registry number 19982-08-2.
• Populate object properties as the semantic relationships linking pairs of entities using the appropriate data source. For example, an object property of type “DRUG_TREATS_DISEASE” links memantine to the instance of Disease named Alzheimer’s Disease.

After populating the AlzKB ontology with entities, relationships, and data properties, we serialized the ontology into the Resource Description Framework (RDF) or XML graph data format, which is compatible with modern graph database software as an input format. A complete list of the data sources used in AlzKB at the time of writing is provided in Table 1 . We then populated a Neo4j graph database (version 4.4.5; Neo4j, Inc) [ 22 ] with the contents of the RDF or XML file using the neosemantics library [ 23 ], which parses the RDF data, inserting semantic triples into the graph database corresponding to each entity or relationship. Finally, we stripped the newly populated graph database of unnecessary artifacts that are components of the OWL 2 standard, leaving only nodes, relationships, and properties defined within the hierarchy. For the publicly hosted version of AlzKB, we created a web server that hosts both the static AlzKB website (containing information, documentation, and use details) and the Neo4j graph database, which is available by navigating to a subdomain [ 24 ] of the main website [ 11 ]. For reproducibility, this entire pipeline (including mappings to source databases) is provided as a single Python script available on GitHub (the most recent version) [ 25 ] or Zenodo (an archived version of the code at the time of publication) [ 26 ].

a As source data elements do not correspond in a 1-to-1 manner with entities in the graph (eg, entities may be merged, filtered, or used as edges rather than nodes), actual counts for entities in AlzKB stratified by source are not available. The sizes are the best available estimates at the time of publication. Table 2 and Table S1 in Multimedia Appendix 1 [ 50 - 56 ] provide actual node and edge type counts in AlzKB.

b AOP-DB: Adverse Outcome Pathway Database.

c The derived data are structured in part using Hetionet.

d AD: Alzheimer disease.

e EPA: Environmental Protection Agency.

f DSSTox: Distributed Structure-Searchable Toxicity.

g ACToR: Aggregated Computational Toxicology Resource.

h GWAS: genome-wide association studies.

i LINCS: Library of Integrated Network-Based Cellular Signatures.

j NCBI: National Center for Biotechnology Information.

k MeSH: Medical Subject Headings.

l SIDER: Side Effect Resource.

m Counts not applicable (TISSUES associations map to edges rather than nodes in the graph).

Validating AlzKB Using Real-World Use Cases

After building AlzKB’s knowledge graph, we designed two ML-based use cases that resemble real-world tasks for which AlzKB was originally designed: (1) proposing genetic targets for new drugs based on disease similarity and topological graph features and (2) predicting new edges in the knowledge graph linking AD to repurposed drugs via a graph completion model. These 2 use cases are intended to assess the external validity of AlzKB—for the ML models to perform well on tasks defined using real-world evaluation end points (eg, effective drugs or etiologically important genes), the informative patterns and phenomena underlying those end points need to be adequately captured in the knowledge graph.

In the first use case (identifying genetic targets via graph topology measures), we trained a random forest (RF) classifier (implemented in the scikit-learn library [Python Software Foundation] for the Python programming language) using the following topological graph features, which are computed for every node pair in the graph (regardless of whether an edge does or does not exist between them): common neighbors, total neighbors, preferential attachment, Adamic-Adar, and resource allocation [ 57 - 60 ]. Each feature gives a different measure of network “relatedness” for a pair of nodes, which are then used as predictive features in the RF model. For a given node pair ( n 1 , n 2 ), these metrics are defined as follows:

where N(n 1 ) is the set of neighbor (adjacent) nodes of node i . Our training procedure for the RF model included 3-fold grid search cross-validation to optimize hyperparameters, an 80%/20% train/test split, and repeating the procedure 10 times with random sampling.

To accomplish the second use case (drug repurposing via graph completion models), we implemented and compared the performance of 5 graph completion algorithms applied to the entire AlzKB knowledge graph. These models learn low-dimensional representations of graph nodes as vector embeddings. The embeddings are then combined to propose all possible triples in the graph (source node, edge, and target node), and scores are generated to indicate the plausibility of the triple. The 5 models we evaluated are TransE, RotatE, DistMult, ComplEx, and ConvE [ 60 ].

We implemented the 5 models using PyKEEN—a Python library for knowledge graph embeddings [ 50 ]. We randomly split the data set of all triples into 80/10/10 training/validation/testing sets and used grid search to empirically set embedding dimensions to 256 and the number of epochs to 100 with early stopping allowed. All remaining hyperparameters were set to the PyKEEN defaults. We trained the models on Google Colab using a single Tesla T4 graphics processing unit and evaluated the results using the rank-based evaluation metrics hits@k ( k =1, 3, and 10) and mean reciprocal rank (MRR) [ 61 ]. Ranking-based evaluation sorts the scores of triples in descending order and sets their rank as the index in the sorted list. In the case of multiple “true” triples having an equal score, we used the average of the most optimistic (best) and pessimistic (worst) ranks across the metrics. Briefly, hits@k is the ratio of true triples in the test set that have been ranked within the top k predictions of the model. Higher values indicate better performance. The MRR, also known as inverse harmonic mean rank, is the arithmetic mean of the inverse rank of the true triples. We performed evaluation on both left- and right-side predictions (ie, how well they can predict missing entities in partial triples without either the head [source] or tail [target] entities).

Ethical Considerations

No human participants were involved in this research. All data used to build and evaluate AlzKB were derived from publicly available biomedical knowledge retrieved from open access databases. None of the data included were derived from individual human participants. Similarly, AlzKB is entirely open source and publicly available and complies with the licensing terms of all 22 source databases used to build the knowledge base.

Knowledge Base Description

The first release of AlzKB (version 1.0) [ 26 ] contains 118,902 distinct nodes (representing biomedical entities) and 1,309,527 relationships linking those nodes. A full summary of node and relationship types with counts, respectively, is provided in Table 2 and Table S1 in Multimedia Appendix 1 . Users can interact with AlzKB in their web browser using the built-in Neo4j interface or programmatically by connecting to the graph database over the internet. We also provide instructions for installing a local copy of the graph database as well as how to build the database from its original data sources.

Proposing New Therapeutic Targets for AD

As a proof of concept, we performed an analysis to predict whether known PD genes are also linked to AD etiology. PD is a chronic, progressive neurological disorder characterized by uncontrollable movements and possible mental and behavioral changes. Similar to AD, the precise etiology of PD is not fully understood, but the disease is characterized by the death or dysfunction of basal ganglia neurons. A growing body of work has established physiological and genetic similarities between PD and AD [ 62 ], and it has been proposed that drugs targeting PD genes could potentially treat AD as well. To approach this hypothesis computationally, we defined a binary classification task to predict whether gene nodes in the AlzKB knowledge graph are or are not AD genes [ 63 ]. To assemble the data set, we considered all gene nodes adjacent to AD as positive (n=101) and all gene nodes not adjacent to AD as negative (n=62,306). The negative samples are assumed to contain a mixture of true negatives and false negatives; in link prediction tasks, the goal is to recover the false negatives. We further filtered the negative nodes to omit PD genes (n=73) and orphan gene nodes (n=43,032) and down sampled the remaining genes to 303 (ie, 3 times the number of positive samples). To evaluate the performance, we used accuracy, balanced accuracy, precision, recall, F 1 -score, area under the receiver operating characteristic curve, and area under the precision-recall curve, as shown in Figure 2 .

The RF model predicted gene-disease relationships with an average balanced accuracy of 96.2% (precision=0.88; recall=0.98). We applied the trained models to predict PD genes that are likely to also be AD genes. Of the 73 PD genes in AlzKB, 8 (11%; FYN , DCTN1 , SNCA , SYNJ1 , RSP12 , ATXN2 , KCNIP3 , and CHRNB1 ; described in Table 3 ) were predicted to be AD genes. A total of 10% (7/73) of the genes were predicted to be AD genes in all 10 models, whereas CHRNB1 was predicted in 7 of the 10 models.

Drug Repurposing via Graph Data Science

As a second use case, we considered the task of repurposing existing drugs—currently used to treat other diseases—based on patterns in the knowledge graph that suggest that they may also treat AD. To do this, we trained 5 state-of-the-art knowledge graph completion methods (TransE, RotatE, DistMult, ComplEx, and ConvE) [ 51 ] on AlzKB and selected the highest-performing one to predict links between drugs and AD. Additional details about the differences between these methods are provided in Multimedia Appendix 1 .

The performance of the 5 different knowledge graph completion models is shown in Table 4 . Among them, RotatE performed best, with the highest MRR and hits@k values. Therefore, we used RotateE to make predictions on the test set to obtain missing head entities with the template ([ drug ], DRUG_TREATS_DISEASE, AD). The top 10 predicted drugs are listed in Table 5 along with their current approved use and relevant clinical trial status pertaining to AD efficacy. Of the top 10 predictions, 3 (30%) have been investigated in clinical trials to treat symptoms of AD. To further explore these predictions, we generated visualizations of a minimum spanning tree linking the 10 drugs to AD in AlzKB’s knowledge graph, as shown in Figure 3 . The visualization shows that the shortest paths between the drugs and AD are mediated by a small set of AD-associated genes, each of which is associated with one or more of the proposed drugs. The visualization is suggestive of interpretable biological mechanisms through which the drugs could act on AD etiology and provides hypotheses to further explore their validity.

a MRR: mean reciprocal rank.

b Italicized values indicate maximum scores within a given column.

a No known AD-related clinical trials for the given drug.

b ER+: estrogen-receptor positive.

Principal Findings

AlzKB is a freely available resource for the biomedical research community, with the primary goal of expanding the repertoire of therapies for AD via drug repurposing. In the previous sections, we described the current contents of AlzKB, the process of constructing it, and 2 specific data-driven use cases that illustrate how it can be applied to drug repurposing tasks. These use cases consisted of predicting the shared genetic architecture of AD and PD (potentially allowing for PD therapies to be repurposed for AD) and directly proposing drugs to repurpose for treating AD by predicting new links between drug and disease nodes in the knowledge graph. In both cases, the results are both biologically plausible and supported by quantitative metrics, yielding new hypotheses that merit experimental validation. AlzKB is a flexible resource that is not limited to these analyses, and we encourage other research teams to use it for different and complementary knowledge discovery tasks.

The Role of AlzKB in Biomedical Knowledge Discovery

AD and other neurodegenerative diseases present one of the greatest challenges in modern biomedicine. AD is by and large a disease of old age, and as improvements to health care continue to increase the overall global life expectancy, we can expect the number of people with various forms of dementia to also increase. As the etiology and pathophysiology of AD are highly multifactorial, there is likely no single “cure” for the disease. Instead, researchers and public health officials have shifted much of their focus toward finding therapies that reduce risk, slow the progression of the disease, or reverse neuronal damage. In addition, as there are various subtypes of AD with underlying mechanisms, any therapy might be effective for only some patients with AD. Therefore, an essential step for reducing global disease burden is to propose many new therapeutic agents that target various aspects of AD pathology. This is precisely the motivating use case for AlzKB. As we have demonstrated, AlzKB provides a rich representation of existing knowledge about AD and the biological context in which it acts. The 2 ML-based use cases we presented previously use real-world end points to demonstrate that the knowledge captured in AlzKB is meaningful and representative of the biological processes underlying the disease. AlzKB stands to become a major resource in the AD research community, where pattern analysis and integration with observational data can be used to propose a diverse array of new therapeutic hypotheses along with interpretable mechanistic explanations of how those therapies may act in the human body.

Building the initial release of AlzKB was a highly interdisciplinary effort involving contributions from experts in translational bioinformatics, data science, and clinical informatics as well as medical scientists. Although each of these domains was essential in delivering a knowledge base that reflects important biomedical patterns describing AD etiology and treatment, a key need during the design and implementation phases was data literacy. To support future work in this and related areas, we encourage the inclusion of informatics and data analysis techniques in all types of biomedical curricula. Beyond AlzKB, our approach for building the knowledge graph is generalizable to practically any domain and depends on (1) defining an ontology using expert knowledge that formally describes the domain of interest and (2) identifying source databases that provide the entities and relationships described in the ontology. We are directly involved in the ongoing development of other knowledge bases using this same approach, including ComptoxAI—a knowledge base that supports AI research in toxicology [ 64 ]. As both knowledge bases share many of the same “core” entities (genes, diseases, pathways, and anatomical structures), the knowledge graphs are already semantically harmonized and ready for integration in larger, cross-disciplinary biomedical knowledge applications.

Discovering Putative Therapies Through Graph Data Science

Of the PD genes predicted to also be AD genes (see the Proposing New Therapeutic Targets for AD section; Table 3 ), some are involved in neuronal signaling and structure, and some are known to be involved in a wide range of neurological disorders. FYN has seen recent attention and investigation into its possible link to AD due to its broad expression in brain tissue and known interactions with tau proteins [ 65 , 66 ]. Among the other identified genes, one ( CHRNB1 ) is known to be involved in acetylcholine signaling [ 67 , 68 ], and another ( KCNIP3 ) codes a protein that interacts with presenilin, and mutations in presenilin are causal for hereditary AD [ 69 , 70 ]. Some of these gene hits ( ATXN2 and DCTN1 ) have limited or no current research directly linking them to AD but are biologically plausible. As such, they may represent novel therapeutic targets or targets for further research and investigation [ 71 ]. For example, DCTN1 encodes the dynactin-1 protein, and deficits in dynactin are connected to several neurodegenerative diseases; however, there is limited research linking this gene to AD [ 72 , 73 ].

Among the drug repurposing predictions (see the Drug Repurposing via Graph Data Science section; Table 5 ) are some agents that have previously been proposed for the treatment of AD (risperidone and sertraline) or for symptoms associated with AD (nicotine). Sumatriptan has been the subject of several studies focused on AD [ 74 ] and is connected to a strong comorbidity of migraine headaches and dementia in women [ 75 ]. Pimozide has been shown to reduce the aggregation of tau protein in mice [ 76 ] and is linked to AD in a number of unrelated in silico models [ 77 ]. The inclusion of nicotine is also noteworthy as it has seen recent interest among AD researchers and is the subject of an ongoing clinical trial to improve memory [ 78 ]. Other drugs listed in Table 5 have not yet been identified as AD treatments and represent novel repurposing candidates. Each can be considered a testable hypothesis meriting further investigation, giving credence to the increased detective power of AlzKB’s knowledge graph approach over existing AD data resources. It should be noted that this approach can only propose new indications for existing drugs and is based on existing knowledge and derived from known biological associations with those drugs. Other approaches (including emerging techniques in graph ML) could be used to propose entirely new drugs that could treat AD.

Future Directions With AlzKB

AlzKB is a growing resource, and we have plans for adding new features and data types that are in various stages of implementation. As a central hypothesis of AD pathogenesis revolves around the atypical accumulation of proteins within and around brain cells, an important step will be to adequately distinguish and differentiate genes from the proteins that those genes code for. Existing data resources available for inclusion in AlzKB largely fail to make this distinction in a way that is accepted by the scientific community, so we are currently evaluating options to use either postprocessing of existing knowledge sources or synthesis of new knowledge to achieve a good representation of genes, proteins, and functional or structural variants that are key to understanding AD.

Current ML models often do not generalize well to heterogeneous graphs such as the one that constitutes AlzKB’s knowledge graph. This is largely because traditional models cannot use the network structure and heterogeneous nature of different entity types. Several promising algorithms can be used for prediction on heterogeneous graphs—including GraphSAGE [ 79 ] and metapath2vec [ 80 ]—but most fail to scale effectively when the number of node or edge types increases. As any effective therapy must be accompanied by a mechanistic understanding of how it functions, we also need to ensure that new heterogeneous graph ML models are explainable . With this in mind, we are using AlzKB as a motivating resource for designing new, cutting-edge algorithms that produce interpretable predictions from highly heterogeneous knowledge graphs. Furthermore, the increasing popularity of large language models (LLMs; such as GPT-4) presents a wealth of opportunities for incorporating knowledge graphs such as AlzKB into diverse AI applications [ 81 ]. One application we are considering is using AlzKB to provide LLMs with formalized knowledge about AD that allows them to more effectively produce informative outputs about AD etiology. Currently, LLMs can perform poorly on technically complex or poorly understood domains due to a scarcity of relevant content in their training corpora, and augmenting their performance using domain-specific knowledge graphs is an emerging strategy for fixing that issue. As we do so, these will be released alongside AlzKB with educational resources that facilitate ease of use and adoptability by various stakeholders.

Knowledge graphs—including AlzKB—come with several important limitations that will be crucial to address in coming years. One of these is the subjective nature of determining what does and does not constitute “knowledge,” implying broad acceptance by the scientific community (as opposed to “data,” which consist of individual observations). Currently, we use expert domain knowledge and careful screening of source databases to accomplish this, but with the advent of broadly accessible generative AI tools, there may be emerging strategies that minimize sources of human bias [ 82 ]. Furthermore, new predictions made using knowledge graphs still necessitate costly and time-consuming experimental or observational follow-up studies to validate those predictions. This is due in part to the absence of negative samples for training predictive models. While the presence of an edge between 2 nodes in a knowledge graph is interpreted as a “positive sample” for model training, the absence of an edge simply means that we do not know whether a relationship does or does not exist, and therefore, it may not in fact be a negative sample. New methods, including self-supervised contrastive learning, show promise in alleviating this issue [ 83 ], but further work is needed to determine whether these generalize well to AlzKB and similar highly heterogeneous biomedical knowledge graphs. Nonetheless, these are active areas of research in the AI, informatics, and computer science communities, and in spite of them, our results are still robust enough to provide compelling evidence demonstrating AlzKB’s scientific value.

Ultimately, we aim to provide AlzKB as a robust resource that helps unravel the etiology of AD. It is already a large, high-quality knowledge base from which graph-based AI or ML approaches can be developed for drug repurposing and drug discovery. As we and the rest of the biomedical research community make these discoveries in the coming years, they will be included and publicized on the AlzKB website as a public resource to drive innovation and scientific progress.

Obtaining AlzKB for Local Use and Extending the Knowledge Graph

As it is a public and open-source resource for scientific discovery, we provide AlzKB through a variety of interfaces with distinct advantages for different use cases and user types. Casual users who wish to browse the knowledge base or perform simple analyses can do so directly through the Neo4j browser interface [ 24 ]. However, for more advanced use cases (or when computational needs exceed those available on the public version of the knowledge base), AlzKB can be either downloaded and populated locally into a Neo4j installation or built from the original source data files via the tools included on the AlzKB GitHub repository [ 25 ]. The latter of these options also allows users to extend the knowledge base to include additional data sources, entity types, or relationships beyond those provided in the official knowledge base distribution. We also encourage users who make modifications to the knowledge base to submit their changes for review to be included in the main code distribution. Instructions for how to contribute to AlzKB are also available on the GitHub repository.

As the data sources included in AlzKB are all, themselves, from open-source databases, we urge users to ensure that any new data sources they merge into AlzKB similarly comply with open-source standards. In brief, AlzKB can only be maintained under the most restrictive license terms of its included third-party sources, so restrictive license terms in a database being considered decrease that database’s suitability for inclusion. We hope for AlzKB to be recognized as a community effort for aggregating and democratizing the discovery of new AD therapeutics and, therefore, encourage public discussion of new methods and data sources to be included.

Conclusions

In this work, we introduced AlzKB as a free, publicly available toolkit and data resource for novel discoveries in AD research, with a particular focus on therapeutic approaches to treating AD. AlzKB is both new and continually growing, and we aim to cultivate a community of researchers to collaboratively increase the impact, speed, and throughput of AD research, along with rapid dissemination to health care, academia, and the pharmaceutical industry. In the future, we will develop new AI and data science methods to continually extract knowledge from AlzKB, but in this study, we already demonstrate through graph data science that AlzKB can both replicate existing AD knowledge and generate entirely new, testable hypotheses to drive the future of drug repurposing and drug discovery.

Acknowledgments

The Alzheimer’s Knowledge Base is supported by US National Institutes of Health grants U01-AG066833, R01-LM010098, R01-LM013463 (principal investigator [PI]: JHM), and R00-LM013646 (PI: JDR).

Data Availability

The data sets generated during and analyzed during this study are available in the GitHub and Zenodo repositories [ 25 , 26 ].

Conflicts of Interest

None declared.

Supplemental information providing expanded details on the knowledge graph completion methods used to validate Alzheimer’s Knowledge Base, as well as counts for relationship types in the knowledge graph.

• 2022 Alzheimer's disease facts and figures. Alzheimers Dement. Apr 2022;18(4):700-789. [ CrossRef ] [ Medline ]
• Yiannopoulou KG, Papageorgiou SG. Current and future treatments in Alzheimer disease: an update. J Cent Nerv Syst Dis. Feb 29, 2020;12:1179573520907397. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Rabinovici GD. Controversy and progress in Alzheimer's disease - FDA approval of aducanumab. N Engl J Med. Aug 26, 2021;385(9):771-774. [ CrossRef ] [ Medline ]
• DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener. Aug 02, 2019;14(1):32. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Aisen PS, Cummings J, Jack CRJ, Morris JC, Sperling R, Frölich L, et al. On the path to 2025: understanding the Alzheimer's disease continuum. Alzheimers Res Ther. Aug 09, 2017;9(1):60. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Fan L, Mao C, Hu X, Zhang S, Yang Z, Hu Z, et al. New insights into the pathogenesis of Alzheimer's disease. Front Neurol. 2019;10:1312. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Silva MV, de Mello Gomide Loures C, Alves LC, de Souza LC, Borges KB, Carvalho MD. Alzheimer's disease: risk factors and potentially protective measures. J Biomed Sci. May 09, 2019;26(1):33. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Rodriguez S, Hug C, Todorov P, Moret N, Boswell SA, Evans K, et al. Machine learning identifies candidates for drug repurposing in Alzheimer's disease. Nat Commun. Feb 15, 2021;12(1):1033. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Tsuji S, Hase T, Yachie-Kinoshita A, Nishino T, Ghosh S, Kikuchi M, et al. Artificial intelligence-based computational framework for drug-target prioritization and inference of novel repositionable drugs for Alzheimer's disease. Alzheimers Res Ther. May 03, 2021;13(1):92. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, et al. Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. Hum Mol Genet. Apr 15, 2007;16(8):865-873. [ CrossRef ] [ Medline ]
• The Alzheimer's KnowledgeBase (AlzKB). AlzKB. URL: https://alzkb.ai/ [accessed 2023-02-24]
• Daluwatumulle G, Wijesinghe R, Weerasinghe R. In silico drug repurposing using knowledge graph embeddings for Alzheimer's disease. In: Proceedings of the 9th International Conference on Bioinformatics Research and Applications. 2022. Presented at: ICBRA '22; September 18-20, 2022; Berlin, Germany. [ CrossRef ]
• Nian Y, Hu X, Zhang R, Feng J, Du J, Li F, et al. Mining on Alzheimer's diseases related knowledge graph to identity potential AD-related semantic triples for drug repurposing. BMC Bioinformatics. Sep 30, 2022;23(Suppl 6):407. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Hsieh KL, Plascencia-Villa G, Lin KH, Perry G, Jiang X, Kim Y. Synthesize heterogeneous biological knowledge via representation learning for Alzheimer's disease drug repurposing. iScience. Nov 26, 2022;26(1):105678. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Binder J, Ursu O, Bologa C, Jiang S, Maphis N, Dadras S, et al. Machine learning prediction and tau-based screening identifies potential Alzheimer's disease genes relevant to immunity. Commun Biol. Feb 11, 2022;5(1):125. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Sügis E, Dauvillier J, Leontjeva A, Adler P, Hindie V, Moncion T, et al. HENA, heterogeneous network-based data set for Alzheimer's disease. Sci Data. Aug 14, 2019;6(1):151. [ CrossRef ] [ Medline ]
• Robinson I, Webber J, Eifrem E. Graph Databases: New Opportunities for Connected Data. Sebastopol, CA. O'Reilly Media; 2015.
• Davis R, Shrobe H, Szolovits P. What is a knowledge representation? AI Mag. 1993;14(1):17. [ CrossRef ]
• Musen MA, Protégé Team. The Protégé project: a look back and a look forward. AI Matters. Jun 2015;1(4):4-12. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Hitzler P, Krötzsch M, Parsia B, Patel-Schneider PF, Rudolph S. OWL 2 Web ontology language primer. World Wide Web Consortium. Apr 21, 2009. URL: https://www.w3.org/TR/2009/WD-owl2-primer-20090421/ [accessed 2024-03-25]
• Tsarkov D, Horrocks I. FaCT++ description logic reasoner: system description. In: Proceedings of the International Joint Conference on Automated Reasoning. 2006. Presented at: IJCAR 2006; August 17-20, 2006; Seattle, WA. [ CrossRef ]
• Neo4j. URL: https://neo4j.com/ [accessed 2022-10-25]
• Barrasa J, Cowley A. neosemantics (n10s): Neo4j RDF and semantics toolkit. Neo4j. URL: https://neo4j.com/labs/neosemantics/ [accessed 2022-10-25]
• Neo4j browser. Neo4j. URL: http://neo4j.alzkb.ai/browser/ [accessed 2023-02-24]
• EpistasisLab/AlzKB. GitHub. URL: https://github.com/EpistasisLab/AlzKB [accessed 2023-02-24]
• Romano J, Wang P. EpistasisLab/AlzKB: AlzKB first DOI release. Zenodo. Aug 22, 2022. URL: https://zenodo.org/records/7015728 [accessed 2024-03-27]
• Mortensen HM, Senn J, Levey T, Langley P, Williams AJ. The 2021 update of the EPA's adverse outcome pathway database. Sci Data. Jul 12, 2021;8(1):169. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Bastian F, Parmentier G, Roux J, Moretti S, Laudet V, Robinson-Rechavi M. Bgee: integrating and comparing heterogeneous transcriptome data among species. In: Proceedings of the Data Integration in the Life Sciences. 2008. Presented at: DILS 2008; June 25-27, 2008; Evry, France. [ CrossRef ]
• Schriml LM, Mitraka E, Munro J, Tauber B, Schor M, Nickle L, et al. Human Disease Ontology 2018 update: classification, content and workflow expansion. Nucleic Acids Res. Jan 08, 2019;47(D1):D955-D962. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Piñero J, Queralt-Rosinach N, Bravo A, Deu-Pons J, Bauer-Mehren A, Baron M, et al. DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database (Oxford). 2015;2015:bav028. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, et al. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. Jan 2008;36(Database issue):D901-D906. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Grulke CM, Williams AJ, Thillanadarajah I, Richard AM. EPA's DSSTox database: history of development of a curated chemistry resource supporting computational toxicology research. Comput Toxicol. Nov 01, 2019;12:100096. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Judson R, Richard A, Dix D, Houck K, Elloumi F, Martin M, et al. ACToR--Aggregated computational toxicology resource. Toxicol Appl Pharmacol. Nov 15, 2008;233(1):7-13. [ CrossRef ] [ Medline ]
• Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. May 2000;25(1):25-29. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Gene Ontology Consortium. The Gene Ontology resource: enriching a GOld mine. Nucleic Acids Res. Jan 08, 2021;49(D1):D325-D334. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Buniello A, MacArthur JA, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. Jan 08, 2019;47(D1):D1005-D1012. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Himmelstein DS, Lizee A, Hessler C, Brueggeman L, Chen SL, Hadley D, et al. Systematic integration of biomedical knowledge prioritizes drugs for repurposing. Elife. Sep 22, 2017;6:e26726. [ FREE Full text ] [ CrossRef ] [ Medline ]
• The human reference protein interactome mapping project. The Human Reference Interactome. URL: http://www.interactome-atlas.org/ [accessed 2023-02-24]
• Duan Q, Reid SP, Clark NR, Wang Z, Fernandez NF, Rouillard AD, et al. L1000CDS: LINCS L1000 characteristic direction signatures search engine. NPJ Syst Biol Appl. Aug 04, 2016;2(1):16015. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Lipscomb CE. Medical Subject Headings (MeSH). Bull Med Libr Assoc. Jul 2000;88(3):265-266. [ FREE Full text ] [ Medline ]
• Maglott D, Ostell J, Pruitt KD, Tatusova T. Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res. Jan 2011;39(Database issue):D52-D57. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Schaefer C, Anthony K, Krupa S, Buchoff J, Day M, Hannay T, et al. PID: the pathway interaction database. Nat Prec. Aug 29, 2008. [ CrossRef ]
• Himmelstein D, Pouya K, Hessler CS, Green AJ, Baranzini S. PharmacotherapyDB 1.0: the open catalog of drug therapies for disease. Figshare. 2016. URL: https://tinyurl.com/mv8k46em [accessed 2024-03-25]
• Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. Jan 08, 2021;49(D1):D1388-D1395. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Wu G, Haw R. Functional interaction network construction and analysis for disease discovery. Methods Mol Biol. 2017;1558:235-253. [ CrossRef ] [ Medline ]
• Kuhn M, Letunic I, Jensen LJ, Bork P. The SIDER database of drugs and side effects. Nucleic Acids Res. Jan 04, 2016;44(D1):D1075-D1079. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Palasca O, Santos A, Stolte C, Gorodkin J, Jensen LJ. TISSUES 2.0: an integrative web resource on mammalian tissue expression. Database (Oxford). Jan 01, 2018;2018:2. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Mungall CJ, Torniai C, Gkoutos GV, Lewis SE, Haendel MA. Uberon, an integrative multi-species anatomy ontology. Genome Biol. Jan 31, 2012;13(1):R5. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Martens M, Ammar A, Riutta A, Waagmeester A, Slenter DN, Hanspers KA, et al. WikiPathways: connecting communities. Nucleic Acids Res. Jan 08, 2021;49(D1):D613-D621. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Ali M, Berrendorf M, Hoyt CT, Vermue L, Sharifzadeh S, Tresp V, et al. PyKEEN 1.0: a python library for training and evaluating knowledge graph embeddings. J Mach Learn Res. 2021;22(82):1-6. [ FREE Full text ]
• Zamini M, Reza H, Rabiei M. A review of knowledge graph completion. Information. Aug 21, 2022;13(8):396. [ CrossRef ]
• Bordes A, Usunier N, Garcia-Duran A, Weston J, Yakhnenko O. Translating embeddings for modeling multi-relational data. In: Proceedings of the 26th International Conference on Neural Information Processing Systems - Volume 2. 2013. Presented at: NIPS'13; December 5-10, 2013; Lake Tahoe, Nevada.
• Sun Z, Deng ZH, Nie JY, Tang J. RotatE: knowledge graph embedding by relational rotation in complex space. arXiv. Preprint posted online February 26, 2019. [ FREE Full text ]
• Yang B, Yih WT, He X, Gao J, Deng L. Embedding entities and relations for learning and inference in knowledge bases. arXiv. Preprint posted online December 20, 2014. [ FREE Full text ]
• Trouillon T, Welbl J, Riedel S, Gaussier E, Bouchard G. Complex embeddings for simple link prediction. arXiv. Preprint posted online June 20, 2016. [ FREE Full text ]
• Dettmers T, Minervini P, Stenetorp P, Riedel S. Convolutional 2D knowledge graph embeddings. arXiv. Preprint posted online July 5, 2017. [ FREE Full text ] [ CrossRef ]
• Newman ME. Clustering and preferential attachment in growing networks. Phys Rev E. Jul 26, 2001;64(2):025102. [ CrossRef ]
• Barabasi AL, Albert R. Emergence of scaling in random networks. Science. Oct 15, 1999;286(5439):509-512. [ CrossRef ] [ Medline ]
• Adamic LA, Adar E. Friends and neighbors on the web. Soc Netw. Jul 2003;25(3):211-230. [ CrossRef ]
• Zhou T, Lü L, Zhang YC. Predicting missing links via local information. Eur Phys J B. Oct 10, 2009;71(4):623-630. [ CrossRef ]
• Gao Z, Ding P, Xu R. KG-Predict: a knowledge graph computational framework for drug repurposing. J Biomed Inform. Aug 2022;132:104133. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med. Apr 03, 2003;348(14):1356-1364. [ CrossRef ] [ Medline ]
• Abbas K, Abbasi A, Dong S, Niu L, Yu L, Chen B, et al. Application of network link prediction in drug discovery. BMC Bioinformatics. Apr 12, 2021;22(1):187. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Romano JD, Hao Y, Moore JH, Penning TM. Automating predictive toxicology using ComptoxAI. Chem Res Toxicol. Aug 15, 2022;35(8):1370-1382. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Iannuzzi F, Sirabella R, Canu N, Maier TJ, Annunziato L, Matrone C. Fyn tyrosine kinase elicits amyloid precursor protein Tyr682 phosphorylation in neurons from Alzheimer's disease patients. Cells. Jul 30, 2020;9(8):1807. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Nygaard HB, van Dyck CH, Strittmatter SM. Fyn kinase inhibition as a novel therapy for Alzheimer's disease. Alzheimers Res Ther. Feb 5, 2014;6(1):8. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Lardenoije R, Roubroeks JA, Pishva E, Leber M, Wagner H, Iatrou A, et al. Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood. Clin Epigenetics. Nov 27, 2019;11(1):164. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Lombardo S, Maskos U. Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment. Neuropharmacology. Sep 2015;96(Pt B):255-262. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Jo DG, Lee JY, Hong YM, Song S, Mook-Jung I, Koh JY, et al. Induction of pro-apoptotic calsenilin/DREAM/KChIP3 in Alzheimer's disease and cultured neurons after amyloid-beta exposure. J Neurochem. Feb 2004;88(3):604-611. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Jin JK, Choi JK, Wasco W, Buxbaum JD, Kozlowski PB, Carp RI, et al. Expression of calsenilin in neurons and astrocytes in the Alzheimer's disease brain. Neuroreport. Apr 04, 2005;16(5):451-455. [ CrossRef ] [ Medline ]
• Rosas I, Martínez C, Clarimón J, Lleó A, Illán-Gala I, Dols-Icardo O, et al. Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease. Neurobiol Aging. Mar 2020;87:139.e1-139.e7. [ CrossRef ] [ Medline ]
• Aboud O, Parcon PA, DeWall KM, Liu L, Mrak RE, Griffin WS. Aging, Alzheimer's, and APOE genotype influence the expression and neuronal distribution patterns of microtubule motor protein dynactin-P50. Front Cell Neurosci. Mar 25, 2015;9:103. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Caroppo P, Le Ber I, Clot F, Rivaud-Péchoux S, Camuzat A, De Septenville A, et al. DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes. JAMA Neurol. Feb 2014;71(2):208-215. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Zochodne DW, Ho LT. Sumatriptan blocks neurogenic inflammation in the peripheral nerve trunk. Neurology. Jan 1994;44(1):161-163. [ CrossRef ] [ Medline ]
• Liu CT, Wu BY, Hung YC, Wang LY, Lee YY, Lin TK, et al. Decreased risk of dementia in migraine patients with traditional Chinese medicine use: a population-based cohort study. Oncotarget. Oct 03, 2017;8(45):79680-79692. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Kim YD, Jeong EI, Nah J, Yoo SM, Lee WJ, Kim Y, et al. Pimozide reduces toxic forms of tau in TauC3 mice via 5' adenosine monophosphate-activated protein kinase-mediated autophagy. J Neurochem. Sep 11, 2017;142(5):734-746. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Kumar S, Chowdhury S, Kumar S. In silico repurposing of antipsychotic drugs for Alzheimer's disease. BMC Neurosci. Oct 27, 2017;18(1):76. [ FREE Full text ] [ CrossRef ] [ Medline ]
• van Duijn CM, Hofman A. Relation between nicotine intake and Alzheimer's disease. BMJ. Jun 22, 1991;302(6791):1491-1494. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Hamilton WL, Ying R, Leskovec J. Inductive representation learning on large graphs. arXiv. Preprint posted online June 7, 2017. [ FREE Full text ]
• Dong Y, Chawla NV, Swami A. metapath2vec: scalable representation learning for heterogeneous networks. In: Proceedings of the 23rd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining. 2017. Presented at: KDD '17; August 13-17, 2017; Halifax, NS. URL: https://dl.acm.org/doi/10.1145/3097983.3098036
• Pan S, Luo L, Wang Y, Chen C, Wang J, Wu X. Unifying large language models and knowledge graphs: a roadmap. arXiv. Preprint posted online June 14, 2023. [ FREE Full text ] [ CrossRef ]
• Zhu Y, Wang X, Chen J, Qiao S, Ou Y, Yao Y, et al. LLMs for knowledge graph construction and reasoning: recent capabilities and future opportunities. arXiv. Preprint posted online May 22, 2023. [ FREE Full text ]
• Kefato ZT, Girdzijauskas S. Self-supervised Graph Neural Networks without explicit negative sampling. arXiv. Preprint posted online March 27, 2021. [ FREE Full text ]

Abbreviations

Edited by T de Azevedo Cardoso; submitted 24.02.23; peer-reviewed by P Dabas, N Mungoli, B Xie, C Sun; comments to author 21.04.23; revised version received 23.06.23; accepted 07.11.23; published 18.04.24.

©Joseph D Romano, Van Truong, Rachit Kumar, Mythreye Venkatesan, Britney E Graham, Yun Hao, Nick Matsumoto, Xi Li, Zhiping Wang, Marylyn D Ritchie, Li Shen, Jason H Moore. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 18.04.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.

This paper is in the following e-collection/theme issue:

Published on 19.4.2024 in Vol 8 (2024)

A Health Information Technology Protocol to Enhance Colorectal Cancer Screening

Authors of this article:

Research Letter

• Adam Baus 1 * , MA, MPH, PhD   ; 
• Dannell D Boatman 2 * , MS, EdD   ; 
• Andrea Calkins 1 * , MPH   ; 
• Cecil Pollard 1 * , MA   ; 
• Mary Ellen Conn 2 * , MS   ; 
• Sujha Subramanian 3 * , MA, PhD   ; 
• Stephenie Kennedy-Rea 2 * , MA, EdD  

1 Department of Social and Behavioral Sciences, School of Public Health, West Virginia University, Morgantown, WV, United States

2 Cancer Prevention and Control, West Virginia University Cancer Institute, Morgantown, WV, United States

3 Implenomics, Dover, DE, United States

*all authors contributed equally

Corresponding Author:

Adam Baus, MA, MPH, PhD

Department of Social and Behavioral Sciences

School of Public Health

West Virginia University

64 Medical Center Drive

PO Box 9190

Morgantown, WV, 26506

United States

Phone: 1 304 293 1083

Fax:1 304 293 6685

Email: [email protected]

This study addresses barriers to electronic health records–based colorectal cancer screening and follow-up in primary care through the development and implementation of a health information technology protocol.

Introduction

Cancer is a pressing global public health problem and the second leading cause of death in the United States, accounting for an estimated 1670 deaths daily [ 1 ]. Colorectal cancer (CRC) is the third most commonly diagnosed cancer, the second leading cause of cancer death worldwide [ 2 ], and the third most common cause of cancer-related deaths in the United States [ 3 ]. More effective use of health information technology (HIT), including electronic health records (EHRs), can aid in improving CRC screening and care [ 4 ]. Studies from as early as the 1990s have shown that EHRs and associated clinical decision support tools have promise in helping with patient care and population health needs [ 5 ]. However, barriers like clinician readiness [ 6 ] and clinical workflow integration [ 7 ] hinder EHRs’ full benefits. This study aims to address barriers to EHR-based CRC screening and follow-up through the development and implementation of a universally applicable EHR protocol tailored to identify and overcome practice workflow and EHR challenges.

This study used a mixed methods approach, involving quantitative and qualitative data collection techniques, conducted across 3 diverse health systems in West Virginia to develop and implement an EHR protocol for CRC screening and follow-up. These health systems were purposefully chosen to encompass diverse sizes, organizational structures, geographic locations, patient demographics, and EHR preferences, thereby supporting the generalizability of the study’s findings. These included a free and charitable clinic, a larger, urban, federally qualified health center, and a smaller, rural, federally qualified health center. Key stakeholders, including health care administrators, clinicians, and information technology personnel, were identified as potential participants. This study was conducted from April 2021 through April 2022. Implementation mapping methodology guided the assessment of current CRC screening practices and the development, implementation, and evaluation of the EHR protocol. Data collection tools were pilot tested in Health System A to assess their reliability, validity, and feasibility, then refined prior to full implementation in Health Systems B and C to ensure quality and effectiveness in data collection. Evaluation of the protocol’s acceptability, appropriateness, and feasibility was conducted using the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Technical issues during the study were resolved collaboratively by the research team and technical staff through troubleshooting, protocol adjustments, and ongoing support.

Ethical Considerations

This study received ethics approval from the West Virginia University Institutional Review Board (protocol number 2107363377).

The development of the EHR protocol involved a collaborative process between the research team and key stakeholders from participating health systems. Initial assessments revealed common challenges in CRC screening and follow-up across the diverse settings, including issues related to data quality, workflow inefficiencies, and underutilization of EHR functionalities. Based on these findings, a draft protocol was formulated, emphasizing strategies to enhance EHR data quality and optimization specifically tailored to address the identified barriers. The protocol comprised three key components: (1) Quality Improvement Activities , guiding clinic staff through a Plan-Do-Study-Act cycle to identify and mitigate data entry errors; (2) EHR Optimization Factors , highlighting specific EHR features supporting CRC screening and follow-up when effectively used; and (3) Health Information Technology Assessment , facilitating structured discussions on EHR use roles, office workflows, knowledge, skills, abilities, challenges, and improvement opportunities.

The developed protocol was implemented in Health Systems B and C following its refinement based on feedback from the development site (Health System A). Implementation involved training sessions for clinic staff on protocol utilization and ongoing support from the research team. Eight staff members from the participating health systems completed the AIM, IAM, and FIM assessments, providing valuable insights into their perceptions of the protocol. The mean scores from AIM (mean 16.00, SD 4.24), IAM (mean 15.80, SD 4.54), and FIM (mean 16.80, SD 4.66) indicate favorable perceptions of protocol feasibility, acceptability, and appropriateness. Qualitative feedback from participants further supported the positive reception of the protocol, with respondents expressing satisfaction with its efficacy and intentions to integrate it into their clinical practices. All respondents indicated that they would use or would consider using the protocol within their clinics again. Open-ended responses included “very pleased with the protocol and leveraging EHR/staff/outreach” and “plan to now identify and track to completion of CRC testing.”

The results demonstrate the successful development and initial implementation of an EHR protocol aimed at enhancing CRC screening in primary care settings. The protocol’s favorable reception by clinic staff, as indicated by high scores on acceptability, appropriateness, and feasibility measures, suggests its potential effectiveness in addressing identified barriers. The diverse representation of health systems and EHR platforms involved in the study enhances the generalizability of findings. Limitations include the small sample size and the focus on a specific geographic region. Future research will assess the protocol’s performance across additional EHR systems and health care settings for enhanced scalability and further evaluate the protocol’s impact on CRC screening outcomes.

Acknowledgments

The authors acknowledge the funding and support from the Research Triangle Institute (grant 1-312-0216648-66244L).

Conflicts of Interest

None declared.

• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. Jan 2022;72(1):7-33. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. Feb 2023;72(2):338-344. [ CrossRef ] [ Medline ]
• Division of Cancer Prevention and Control. Colorectal cancer statistics. Centers for Disease Control and Prevention. 2023. URL: https://www.cdc.gov/cancer/colorectal/statistics/index.htm [accessed 2023-12-04]
• Baus A, Wright L, Kennedy-Rea S, Conn ME, Eason S, Boatman D, et al. Leveraging electronic health records data for enhanced colorectal cancer screening efforts. J Appalach Health. 2020;2(4):53-63. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Atasoy H, Greenwood BN, McCullough JS. The digitization of patient care: a review of the effects of electronic health records on health care quality and utilization. Annu Rev Public Health. Apr 01, 2019;40(1):487-500. [ FREE Full text ] [ CrossRef ] [ Medline ]
• Bates DW. Physicians and ambulatory electronic health records. Health Aff (Millwood). Sep 2005;24(5):1180-1189. [ CrossRef ] [ Medline ]
• Hersh W, Weiner M, Embi P, Logan JR, Payne PRO, Bernstam EV, et al. Caveats for the use of operational electronic health record data in comparative effectiveness research. Med Care. Aug 2013;51(8 Suppl 3):S30-S37. [ FREE Full text ] [ CrossRef ] [ Medline ]

Abbreviations

Edited by A Mavragani; submitted 08.12.23; peer-reviewed by Y Chu, A Banerjee; comments to author 05.02.24; revised version received 12.02.24; accepted 04.04.24; published 19.04.24.

©Adam Baus, Dannell D Boatman, Andrea Calkins, Cecil Pollard, Mary Ellen Conn, Sujha Subramanian, Stephenie Kennedy-Rea. Originally published in JMIR Formative Research (https://formative.jmir.org), 19.04.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Formative Research, is properly cited. The complete bibliographic information, a link to the original publication on https://formative.jmir.org, as well as this copyright and license information must be included.