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      in Data Management & Statistics

      How machine learning models can amplify inequities in medical diagnosis and treatment

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      Prior to receiving a PhD in computer science from MIT in 2017, Marzyeh Ghassemi had already begun to wonder whether the use of AI techniques might enhance the biases that already existed in health care. She was one of the early researchers to take up this issue, and she’s been exploring it ever since. In a new paper, Ghassemi, now an assistant professor in MIT’s Department of Electrical Science and Engineering (EECS), and three collaborators based at the Computer Science and Artificial Intelligence Laboratory, have probed the roots of the disparities that can arise in machine learning, often causing models that perform well overall to falter when it comes to subgroups for which relatively few data have been collected and utilized in the training process. The paper — written by two MIT PhD students, Yuzhe Yang and Haoran Zhang, EECS computer scientist Dina Katabi (the Thuan and Nicole Pham Professor), and Ghassemi — was presented last month at the 40th International Conference on Machine Learning in Honolulu, Hawaii.

      In their analysis, the researchers focused on “subpopulation shifts” — differences in the way machine learning models perform for one subgroup as compared to another. “We want the models to be fair and work equally well for all groups, but instead we consistently observe the presence of shifts among different groups that can lead to inferior medical diagnosis and treatment,” says Yang, who along with Zhang are the two lead authors on the paper. The main point of their inquiry is to determine the kinds of subpopulation shifts that can occur and to uncover the mechanisms behind them so that, ultimately, more equitable models can be developed.

      The new paper “significantly advances our understanding” of the subpopulation shift phenomenon, claims Stanford University computer scientist Sanmi Koyejo. “This research contributes valuable insights for future advancements in machine learning models’ performance on underrepresented subgroups.”

      Camels and cattle

      The MIT group has identified four principal types of shifts — spurious correlations, attribute imbalance, class imbalance, and attribute generalization — which, according to Yang, “have never been put together into a coherent and unified framework. We’ve come up with a single equation that shows you where biases can come from.”

      Biases can, in fact, stem from what the researchers call the class, or from the attribute, or both. To pick a simple example, suppose the task assigned to the machine learning model is to sort images of objects — animals in this case — into two classes: cows and camels. Attributes are descriptors that don’t specifically relate to the class itself. It might turn out, for instance, that all the images used in the analysis show cows standing on grass and camels on sand — grass and sand serving as the attributes here. Given the data available to it, the machine could reach an erroneous conclusion — namely that cows can only be found on grass, not on sand, with the opposite being true for camels. Such a finding would be incorrect, however, giving rise to a spurious correlation, which, Yang explains, is a “special case” among subpopulation shifts — “one in which you have a bias in both the class and the attribute.”

      In a medical setting, one could rely on machine learning models to determine whether a person has pneumonia or not based on an examination of X-ray images. There would be two classes in this situation, one consisting of people who have the lung ailment, another for those who are infection-free. A relatively straightforward case would involve just two attributes: the people getting X-rayed are either female or male. If, in this particular dataset, there were 100 males diagnosed with pneumonia for every one female diagnosed with pneumonia, that could lead to an attribute imbalance, and the model would likely do a better job of correctly detecting pneumonia for a man than for a woman. Similarly, having 1,000 times more healthy (pneumonia-free) subjects than sick ones would lead to a class imbalance, with the model biased toward healthy cases. Attribute generalization is the last shift highlighted in the new study. If your sample contained 100 male patients with pneumonia and zero female subjects with the same illness, you still would like the model to be able to generalize and make predictions about female subjects even though there are no samples in the training data for females with pneumonia.

      The team then took 20 advanced algorithms, designed to carry out classification tasks, and tested them on a dozen datasets to see how they performed across different population groups. They reached some unexpected conclusions: By improving the “classifier,” which is the last layer of the neural network, they were able to reduce the occurrence of spurious correlations and class imbalance, but the other shifts were unaffected. Improvements to the “encoder,” one of the uppermost layers in the neural network, could reduce the problem of attribute imbalance. “However, no matter what we did to the encoder or classifier, we did not see any improvements in terms of attribute generalization,” Yang says, “and we don’t yet know how to address that.”

      Precisely accurate

      There is also the question of assessing how well your model actually works in terms of evenhandedness among different population groups. The metric normally used, called worst-group accuracy or WGA, is based on the assumption that if you can improve the accuracy — of, say, medical diagnosis — for the group that has the worst model performance, you would have improved the model as a whole. “The WGA is considered the gold standard in subpopulation evaluation,” the authors contend, but they made a surprising discovery: boosting worst-group accuracy results in a decrease in what they call “worst-case precision.” In medical decision-making of all sorts, one needs both accuracy — which speaks to the validity of the findings — and precision, which relates to the reliability of the methodology. “Precision and accuracy are both very important metrics in classification tasks, and that is especially true in medical diagnostics,” Yang explains. “You should never trade precision for accuracy. You always need to balance the two.”

      The MIT scientists are putting their theories into practice. In a study they’re conducting with a medical center, they’re looking at public datasets for tens of thousands of patients and hundreds of thousands of chest X-rays, trying to see whether it’s possible for machine learning models to work in an unbiased manner for all populations. That’s still far from the case, even though more awareness has been drawn to this problem, Yang says. “We are finding many disparities across different ages, gender, ethnicity, and intersectional groups.”

      He and his colleagues agree on the eventual goal, which is to achieve fairness in health care among all populations. But before we can reach that point, they maintain, we still need a better understanding of the sources of unfairness and how they permeate our current system. Reforming the system as a whole will not be easy, they acknowledge. In fact, the title of the paper they introduced at the Honolulu conference, “Change is Hard,” gives some indications as to the challenges that they and like-minded researchers face. More

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      Summer research offers a springboard to advanced studies

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      Doctoral studies at MIT aren’t a calling for everyone, but they can be for anyone who has had opportunities to discover that science and technology research is their passion and to build the experience and skills to succeed. For Taylor Baum, Josefina Correa Menéndez, and Karla Alejandra Montejo, three graduate students in just one lab of The Picower Institute for Learning and Memory, a pivotal opportunity came via the MIT Summer Research Program in Biology and Neuroscience (MSRP-Bio). When a student finds MSRP-Bio, it helps them find their future in research. 

      In the program, undergraduate STEM majors from outside MIT spend the summer doing full-time research in the departments of Biology, Brain and Cognitive Sciences (BCS), or the Center for Brains, Minds and Machines (CBMM). They gain lab skills, mentoring, preparation for graduate school, and connections that might last a lifetime. Over the last two decades, a total of 215 students from underrepresented minority groups, who are from economically disadvantaged backgrounds, first-generation or nontraditional college students, or students with disabilities have participated in research in BCS or CBMM labs.  

      Like Baum, Correa Menéndez, and Montejo, the vast majority go on to pursue graduate studies, says Diversity and Outreach Coordinator Mandana Sassanfar, who runs the program. For instance, among 91 students who have worked in Picower Institute labs, 81 have completed their undergraduate studies. Of those, 46 enrolled in PhD programs at MIT or other schools such as Cornell, Yale, Stanford, and Princeton universities, and the University of California System. Another 12 have gone to medical school, another seven are in MD/PhD programs, and three have earned master’s degrees. The rest are studying as post-baccalaureates or went straight into the workforce after earning their bachelor’s degree. 

      After participating in the program, Baum, Correa Menéndez, and Montejo each became graduate students in the research group of Emery N. Brown, the Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering in The Picower Institute and the Institute for Medical Engineering and Science. The lab combines statistical, computational, and experimental neuroscience methods to study how general anesthesia affects the central nervous system to ultimately improve patient care and advance understanding of the brain. Brown says the students have each been doing “off-the-scale” work, in keeping with the excellence he’s seen from MSRP BIO students over the years. For example, on Aug. 10 Baum and Correa Menéndez were honored with MathWorks Fellowships.

      “I think MSRP is fantastic. Mandana does this amazing job of getting students who are quite talented to come to MIT to realize that they can move their game to the next level. They have the capacity to do it. They just need the opportunities,” Brown says. “These students live up to the expectations that you have of them. And now as graduate students, they’re taking on hard problems and they’re solving them.” 

      Paths to PhD studies 

      Pursuing a PhD is hardly a given. Many young students have never considered graduate school or specific fields of study like neuroscience or electrical engineering. But Sassanfar engages students across the country to introduce them to the opportunity MSRP-Bio provides to gain exposure, experience, and mentoring in advanced fields. Every fall, after the program’s students have returned to their undergraduate institutions, she visits schools in places as far flung as Florida, Maryland, Puerto Rico, and Texas and goes to conferences for diverse science communities such as ABRCMS and SACNAS to spread the word. 

      Taylor Baum

      Photo courtesy of Taylor Baum.

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      When Baum first connected with the program in 2017, she was finding her way at Penn State University. She had been majoring in biology and music composition but had just switched the latter to engineering following a conversation over coffee exposing her to brain-computer interfacing technology, in which detecting brain signals of people with full-body paralysis could improve their quality of life by enabling control of computers or wheelchairs. Baum became enthusiastic about the potential to build similar systems, but as a new engineering student, she struggled to find summer internships and research opportunities. 

      “I got rejected from every single progam except the MIT Center for Brains, Minds and Machines MSRP,” she recalls with a chuckle. 

      Baum thrived in MSRP-Bio, working in Brown’s lab for three successive summers. At each stage, she said, she gained more research skills, experience, and independence. When she graduated, she was sure she wanted to go to graduate school and applied to four of her dream schools. She accepted MIT’s offer to join the Department of Electrical Engineering and Computer Science, where she is co-advised by faculty members there and by Brown. She is now working to develop a system grounded in cardiovascular physiology that can improve blood pressure management. A tool for practicing anesthesiologists, the system automates the dosing of drugs to maintain a patient’s blood pressure at safe levels in the operating room or intensive care unit. 

      More than that, Baum not only is leading an organization advancing STEM education in Puerto Rico, but also is helping to mentor a current MSRP-Bio student in the Brown lab. 

      “MSRP definitely bonds everyone who has participated in it,” Baum says. “If I see anyone who I know participated in MSRP, we could have an immediate conversation. I know that most of us, if we needed help, we’d feel comfortable asking for help from someone from MSRP. With that shared experience, we have a sense of camaraderie, and community.” 

      In fact, a few years ago when a former MSRP-Bio student named Karla Montejo was applying to MIT, Baum provided essential advice and feedback about the application process, Montejo says. Now, as a graduate student, Montejo has become a mentor for the program in her own right, Sassanfar notes. For instance, Montejo serves on program alumni panels that advise new MSRP-Bio students. 

      Karla Alejandra Montejo

      Photo courtesy of Karla Alejandra Montejo.

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      Montejo’s family immigrated to Miami from Cuba when she was a child. The magnet high school she attended was so new that students were encouraged to help establish the school’s programs. She forged a path into research. 

      “I didn’t even know what research was,” she says. “I wanted to be a doctor, and I thought maybe it would help me on my resume. I thought it would be kind of like shadowing, but no, it was really different. So I got really captured by research when I was in high school.” 

      Despite continuing to pursue research in college at Florida International University, Montejo didn’t get into graduate school on her first attempt because she hadn’t yet learned how to focus her application. But Sassanfar had visited FIU to recruit students and through that relationship Montejo had already gone through MIT’s related Quantitative Methods Workshop (QMW). So Montejo enrolled in MSRP-Bio, working in the CBMM-affiliated lab of Gabriel Kreiman at Boston Children’s Hospital. 

      “I feel like Mandana really helped me out, gave me a break, and the MSRP experience pretty much solidified that I really wanted to come to MIT,” Montejo says. 

      In the QMW, Montejo learned she really liked computational neuroscience, and in Kreiman’s lab she got to try her hand at computational modeling of the cognition involved in making perceptual sense of complex scenes. Montejo realized she wanted to work on more biologically based neuroscience problems. When the summer ended, because she was off the normal graduate school cycle for now, she found a two-year post-baccalaurate program at Mayo Clinic studying the role a brain cell type called astrocytes might have in the Parkinson’s disease treatment deep brain stimulation. 

      When it came time to reapply to graduate schools (with the help of Baum and others in the BCS Application Assistance Program) Montejo applied to MIT and got in, joining the Brown lab. Now she’s working on modeling the role of  metabolic processes in the changing of brain rhythms under anesthesia, taking advantage of how general anesthesia predictably changes brain states. The effects anesthetic drugs have on cell metabolism and the way that ultimately affects levels of consciousness reveals important aspects of how metabolism affects brain circuits and systems. Earlier this month, for instance, Montejo co-led a paper the lab published in The Proceedings of the National Academy of Sciences detailing the neuroscience of a patient’s transition into an especially deep state of unconsciousness called “burst suppression.” 

      Josefina Correa Menendez

      Photo: David Orenstein

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      A signature of the Brown lab’s work is rigorous statistical analysis and methods, for instance to discern brain arousal states from EEG measures of brain rhythms. A PhD candidate in MIT’s Interdisciplinary Doctoral Program in Statistics, Correa Menéndez is advancing the use of Bayesian hierarchical models for neural data analysis. These statistical models offer a principled way of pooling information across datasets. One of her models can help scientists better understand the way neurons can “spike” with electrical activity when the brain is presented with a stimulus. The other’s power is in discerning critical features such as arousal states of the brain under general anesthesia from electrophysiological recordings. 

      Though she now works with complex equations and computations as a PhD candidate in neuroscience and statistics, Correa Menéndez was mostly interested in music art as a high school student at Academia María Reina in San Juan and then architecture in college at the University of Puerto Rico at Río Piedras. It was discussions at the intersection of epistemology and art during an art theory class that inspired Correa Menéndez to switch her major to biology and to take computer science classes, too. 

      When Sassanfar visited Puerto Rico in 2017, a computer science professor (Patricia Ordóñez) suggested that Correa Menéndez apply for a chance to attend the QMW. She did, and that led her to also participate in MSRP-Bio in the lab of Sherman Fairchild Professor Matt Wilson (a faculty member in BCS, CBMM, and the Picower Institute). She joined in the lab’s studies of how spatial memories are represented in the hippocampus and how the brain makes use of those memories to help understand the world around it. With mentoring from then-postdoc Carmen Varela (now a faculty member at Florida State University), the experience not only exposed her to neuroscience, but also helped her gain skills and experience with lab experiments, building research tools, and conducting statistical analyses. She ended up working in the Wilson lab as a research scholar for a year and began her graduate studies in September 2018.  

      Classes she took with Brown as a research scholar inspired her to join his lab as a graduate student. 

      “Taking the classes with Emery and also doing experiments made me aware of the role of statistics in the scientific process: from the interpretation of results to the analysis and the design of experiments,” she says. “More often than not, in science, statistics becomes this sort of afterthought — this ‘annoying’ thing that people need to do to get their paper published. But statistics as a field is actually a lot more than that. It’s a way of thinking about data. Particularly, Bayesian modeling provides a principled inference framework for combining prior knowledge into a hypothesis that you can test with data.” 

      To be sure, no one starts out with such inspiration about scientific scholarship, but MSRP-Bio helps students find that passion for research and the paths that opens up.   More

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      Making sense of cell fate

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      Despite the proliferation of novel therapies such as immunotherapy or targeted therapies, radiation and chemotherapy remain the frontline treatment for cancer patients. About half of all patients still receive radiation and 60-80 percent receive chemotherapy.

      Both radiation and chemotherapy work by damaging DNA, taking advantage of a vulnerability specific to cancer cells. Healthy cells are more likely to survive radiation and chemotherapy since their mechanisms for identifying and repairing DNA damage are intact. In cancer cells, these repair mechanisms are compromised by mutations. When cancer cells cannot adequately respond to the DNA damage caused by radiation and chemotherapy, ideally, they undergo apoptosis or die by other means.

      However, there is another fate for cells after DNA damage: senescence — a state where cells survive, but stop dividing. Senescent cells’ DNA has not been damaged enough to induce apoptosis but is too damaged to support cell division. While senescent cancer cells themselves are unable to proliferate and spread, they are bad actors in the fight against cancer because they seem to enable other cancer cells to develop more aggressively. Although a cancer cell’s fate is not apparent until a few days after treatment, the decision to survive, die, or enter senescence is made much earlier. But, precisely when and how that decision is made has not been well understood.

      In an open-access study of ovarian and osteosarcoma cancer cells appearing July 19 in Cell Systems, MIT researchers show that cell signaling proteins commonly associated with cell proliferation and apoptosis instead commit cancer cells to senescence within 12 hours of treatment with low doses of certain kinds of chemotherapy.

      “When it comes to treating cancer, this study underscores that it’s important not to think too linearly about cell signaling,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study. “If you assume that a particular treatment will always affect cancer cell signaling in the same way — you may be setting yourself up for many surprises, and treating cancers with the wrong combination of drugs.”

      Using a combination of experiments with cancer cells and computational modeling, the team investigated the cell signaling mechanisms that prompt cancer cells to enter senescence after treatment with a commonly used anti-cancer agent. Their efforts singled out two protein kinases and a component of the AP-1 transcription factor complex as highly associated with the induction of senescence after DNA damage, despite the well-established roles for all of these molecules in promoting cell proliferation in cancer.

      The researchers treated cancer cells with low and high doses of doxorubicin, a chemotherapy that interferes with the function with topoisomerase II, an enzyme that breaks and then repairs DNA strands during replication to fix tangles and other topological problems.

      By measuring the effects of DNA damage on single cells at several time points ranging from six hours to four days after the initial exposure, the team created two datasets. In one dataset, the researchers tracked cell fate over time. For the second set, researchers measured relative cell signaling activity levels across a variety of proteins associated with responses to DNA damage or cellular stress, determination of cell fate, and progress through cell growth and division.

      The two datasets were used to build a computational model that identifies correlations between time, dosage, signal, and cell fate. The model identified the activities of the MAP kinases Erk and JNK, and the transcription factor c-Jun as key components of the AP-1 protein likewise understood to involved in the induction of senescence. The researchers then validated these computational findings by showing that inhibition of JNK and Erk after DNA damage successfully prevented cells from entering senescence.

      The researchers leveraged JNK and Erk inhibition to pinpoint exactly when cells made the decision to enter senescence. Surprisingly, they found that the decision to enter senescence was made within 12 hours of DNA damage, even though it took days to actually see the senescent cells accumulate. The team also found that with the passage of more time, these MAP kinases took on a different function: promoting the secretion of proinflammatory proteins called cytokines that are responsible for making other cancer cells proliferate and develop resistance to chemotherapy.

      “Proteins like cytokines encourage ‘bad behavior’ in neighboring tumor cells that lead to more aggressive cancer progression,” says Tatiana Netterfield, a graduate student in the Yaffe lab and the lead author of the study. “Because of this, it is thought that senescent cells that stay near the tumor for long periods of time are detrimental to treating cancer.”

      This study’s findings apply to cancer cells treated with a commonly used type of chemotherapy that stalls DNA replication after repair. But more broadly, the study emphasizes that “when treating cancer, it’s extremely important to understand the molecular characteristics of cancer cells and the contextual factors such as time and dosing that determine cell fate,” explains Netterfield.

      The study, however, has more immediate implications for treatments that are already in use. One class of Erk inhibitors, MEK inhibitors, are used in the clinic with the expectation that they will curb cancer growth.

      “We must be cautious about administering MEK inhibitors together with chemotherapies,” says Yaffe. “The combination may have the unintended effect of driving cells into proliferation, rather than senescence.”

      In future work, the team will perform studies to understand how and why individual cells choose to proliferate instead of enter senescence. Additionally, the team is employing next-generation sequencing to understand which genes c-Jun is regulating in order to push cells toward senescence.

      This study was funded, in part, by the Charles and Marjorie Holloway Foundation and the MIT Center for Precision Cancer Medicine. More

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      Joining the battle against health care bias

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      Medical researchers are awash in a tsunami of clinical data. But we need major changes in how we gather, share, and apply this data to bring its benefits to all, says Leo Anthony Celi, principal research scientist at the MIT Laboratory for Computational Physiology (LCP). 

      One key change is to make clinical data of all kinds openly available, with the proper privacy safeguards, says Celi, a practicing intensive care unit (ICU) physician at the Beth Israel Deaconess Medical Center (BIDMC) in Boston. Another key is to fully exploit these open data with multidisciplinary collaborations among clinicians, academic investigators, and industry. A third key is to focus on the varying needs of populations across every country, and to empower the experts there to drive advances in treatment, says Celi, who is also an associate professor at Harvard Medical School. 

      In all of this work, researchers must actively seek to overcome the perennial problem of bias in understanding and applying medical knowledge. This deeply damaging problem is only heightened with the massive onslaught of machine learning and other artificial intelligence technologies. “Computers will pick up all our unconscious, implicit biases when we make decisions,” Celi warns.

      Play video

      Sharing medical data 

      Founded by the LCP, the MIT Critical Data consortium builds communities across disciplines to leverage the data that are routinely collected in the process of ICU care to understand health and disease better. “We connect people and align incentives,” Celi says. “In order to advance, hospitals need to work with universities, who need to work with industry partners, who need access to clinicians and data.” 

      The consortium’s flagship project is the MIMIC (medical information marked for intensive care) ICU database built at BIDMC. With about 35,000 users around the world, the MIMIC cohort is the most widely analyzed in critical care medicine. 

      International collaborations such as MIMIC highlight one of the biggest obstacles in health care: most clinical research is performed in rich countries, typically with most clinical trial participants being white males. “The findings of these trials are translated into treatment recommendations for every patient around the world,” says Celi. “We think that this is a major contributor to the sub-optimal outcomes that we see in the treatment of all sorts of diseases in Africa, in Asia, in Latin America.” 

      To fix this problem, “groups who are disproportionately burdened by disease should be setting the research agenda,” Celi says. 

      That’s the rule in the “datathons” (health hackathons) that MIT Critical Data has organized in more than two dozen countries, which apply the latest data science techniques to real-world health data. At the datathons, MIT students and faculty both learn from local experts and share their own skill sets. Many of these several-day events are sponsored by the MIT Industrial Liaison Program, the MIT International Science and Technology Initiatives program, or the MIT Sloan Latin America Office. 

      Datathons are typically held in that country’s national language or dialect, rather than English, with representation from academia, industry, government, and other stakeholders. Doctors, nurses, pharmacists, and social workers join up with computer science, engineering, and humanities students to brainstorm and analyze potential solutions. “They need each other’s expertise to fully leverage and discover and validate the knowledge that is encrypted in the data, and that will be translated into the way they deliver care,” says Celi. 

      “Everywhere we go, there is incredible talent that is completely capable of designing solutions to their health-care problems,” he emphasizes. The datathons aim to further empower the professionals and students in the host countries to drive medical research, innovation, and entrepreneurship.

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      Fighting built-in bias 

      Applying machine learning and other advanced data science techniques to medical data reveals that “bias exists in the data in unimaginable ways” in every type of health product, Celi says. Often this bias is rooted in the clinical trials required to approve medical devices and therapies. 

      One dramatic example comes from pulse oximeters, which provide readouts on oxygen levels in a patient’s blood. It turns out that these devices overestimate oxygen levels for people of color. “We have been under-treating individuals of color because the nurses and the doctors have been falsely assured that their patients have adequate oxygenation,” he says. “We think that we have harmed, if not killed, a lot of individuals in the past, especially during Covid, as a result of a technology that was not designed with inclusive test subjects.” 

      Such dangers only increase as the universe of medical data expands. “The data that we have available now for research is maybe two or three levels of magnitude more than what we had even 10 years ago,” Celi says. MIMIC, for example, now includes terabytes of X-ray, echocardiogram, and electrocardiogram data, all linked with related health records. Such enormous sets of data allow investigators to detect health patterns that were previously invisible. 

      “But there is a caveat,” Celi says. “It is trivial for computers to learn sensitive attributes that are not very obvious to human experts.” In a study released last year, for instance, he and his colleagues showed that algorithms can tell if a chest X-ray image belongs to a white patient or person of color, even without looking at any other clinical data. 

      “More concerningly, groups including ours have demonstrated that computers can learn easily if you’re rich or poor, just from your imaging alone,” Celi says. “We were able to train a computer to predict if you are on Medicaid, or if you have private insurance, if you feed them with chest X-rays without any abnormality. So again, computers are catching features that are not visible to the human eye.” And these features may lead algorithms to advise against therapies for people who are Black or poor, he says. 

      Opening up industry opportunities 

      Every stakeholder stands to benefit when pharmaceutical firms and other health-care corporations better understand societal needs and can target their treatments appropriately, Celi says. 

      “We need to bring to the table the vendors of electronic health records and the medical device manufacturers, as well as the pharmaceutical companies,” he explains. “They need to be more aware of the disparities in the way that they perform their research. They need to have more investigators representing underrepresented groups of people, to provide that lens to come up with better designs of health products.” 

      Corporations could benefit by sharing results from their clinical trials, and could immediately see these potential benefits by participating in datathons, Celi says. “They could really witness the magic that happens when that data is curated and analyzed by students and clinicians with different backgrounds from different countries. So we’re calling out our partners in the pharmaceutical industry to organize these events with us!”  More

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      Researchers develop novel AI-based estimator for manufacturing medicine

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      When medical companies manufacture the pills and tablets that treat any number of illnesses, aches, and pains, they need to isolate the active pharmaceutical ingredient from a suspension and dry it. The process requires a human operator to monitor an industrial dryer, agitate the material, and watch for the compound to take on the right qualities for compressing into medicine. The job depends heavily on the operator’s observations.   

      Methods for making that process less subjective and a lot more efficient are the subject of a recent Nature Communications paper authored by researchers at MIT and Takeda. The paper’s authors devise a way to use physics and machine learning to categorize the rough surfaces that characterize particles in a mixture. The technique, which uses a physics-enhanced autocorrelation-based estimator (PEACE), could change pharmaceutical manufacturing processes for pills and powders, increasing efficiency and accuracy and resulting in fewer failed batches of pharmaceutical products.  

      “Failed batches or failed steps in the pharmaceutical process are very serious,” says Allan Myerson, a professor of practice in the MIT Department of Chemical Engineering and one of the study’s authors. “Anything that improves the reliability of the pharmaceutical manufacturing, reduces time, and improves compliance is a big deal.”

      The team’s work is part of an ongoing collaboration between Takeda and MIT, launched in 2020. The MIT-Takeda Program aims to leverage the experience of both MIT and Takeda to solve problems at the intersection of medicine, artificial intelligence, and health care.

      In pharmaceutical manufacturing, determining whether a compound is adequately mixed and dried ordinarily requires stopping an industrial-sized dryer and taking samples off the manufacturing line for testing. Researchers at Takeda thought artificial intelligence could improve the task and reduce stoppages that slow down production. Originally the research team planned to use videos to train a computer model to replace a human operator. But determining which videos to use to train the model still proved too subjective. Instead, the MIT-Takeda team decided to illuminate particles with a laser during filtration and drying, and measure particle size distribution using physics and machine learning. 

      “We just shine a laser beam on top of this drying surface and observe,” says Qihang Zhang, a doctoral student in MIT’s Department of Electrical Engineering and Computer Science and the study’s first author. 

      Play video

      A physics-derived equation describes the interaction between the laser and the mixture, while machine learning characterizes the particle sizes. The process doesn’t require stopping and starting the process, which means the entire job is more secure and more efficient than standard operating procedure, according to George Barbastathis, professor of mechanical engineering at MIT and corresponding author of the study.

      The machine learning algorithm also does not require many datasets to learn its job, because the physics allows for speedy training of the neural network.

      “We utilize the physics to compensate for the lack of training data, so that we can train the neural network in an efficient way,” says Zhang. “Only a tiny amount of experimental data is enough to get a good result.”

      Today, the only inline processes used for particle measurements in the pharmaceutical industry are for slurry products, where crystals float in a liquid. There is no method for measuring particles within a powder during mixing. Powders can be made from slurries, but when a liquid is filtered and dried its composition changes, requiring new measurements. In addition to making the process quicker and more efficient, using the PEACE mechanism makes the job safer because it requires less handling of potentially highly potent materials, the authors say. 

      The ramifications for pharmaceutical manufacturing could be significant, allowing drug production to be more efficient, sustainable, and cost-effective, by reducing the number of experiments companies need to conduct when making products. Monitoring the characteristics of a drying mixture is an issue the industry has long struggled with, according to Charles Papageorgiou, the director of Takeda’s Process Chemistry Development group and one of the study’s authors. 

      “It is a problem that a lot of people are trying to solve, and there isn’t a good sensor out there,” says Papageorgiou. “This is a pretty big step change, I think, with respect to being able to monitor, in real time, particle size distribution.”

      Papageorgiou said that the mechanism could have applications in other industrial pharmaceutical operations. At some point, the laser technology may be able to train video imaging, allowing manufacturers to use a camera for analysis rather than laser measurements. The company is now working to assess the tool on different compounds in its lab. 

      The results come directly from collaboration between Takeda and three MIT departments: Mechanical Engineering, Chemical Engineering, and Electrical Engineering and Computer Science. Over the last three years, researchers at MIT and Takeda have worked together on 19 projects focused on applying machine learning and artificial intelligence to problems in the health-care and medical industry as part of the MIT-Takeda Program. 

      Often, it can take years for academic research to translate to industrial processes. But researchers are hopeful that direct collaboration could shorten that timeline. Takeda is a walking distance away from MIT’s campus, which allowed researchers to set up tests in the company’s lab, and real-time feedback from Takeda helped MIT researchers structure their research based on the company’s equipment and operations. 

      Combining the expertise and mission of both entities helps researchers ensure their experimental results will have real-world implications. The team has already filed for two patents and has plans to file for a third.   More

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      3 Questions: Leo Anthony Celi on ChatGPT and medicine

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      Launched in November 2022, ChatGPT is a chatbot that can not only engage in human-like conversation, but also provide accurate answers to questions in a wide range of knowledge domains. The chatbot, created by the firm OpenAI, is based on a family of “large language models” — algorithms that can recognize, predict, and generate text based on patterns they identify in datasets containing hundreds of millions of words.

      In a study appearing in PLOS Digital Health this week, researchers report that ChatGPT performed at or near the passing threshold of the U.S. Medical Licensing Exam (USMLE) — a comprehensive, three-part exam that doctors must pass before practicing medicine in the United States. In an editorial accompanying the paper, Leo Anthony Celi, a principal research scientist at MIT’s Institute for Medical Engineering and Science, a practicing physician at Beth Israel Deaconess Medical Center, and an associate professor at Harvard Medical School, and his co-authors argue that ChatGPT’s success on this exam should be a wake-up call for the medical community.

      Q: What do you think the success of ChatGPT on the USMLE reveals about the nature of the medical education and evaluation of students? 

      A: The framing of medical knowledge as something that can be encapsulated into multiple choice questions creates a cognitive framing of false certainty. Medical knowledge is often taught as fixed model representations of health and disease. Treatment effects are presented as stable over time despite constantly changing practice patterns. Mechanistic models are passed on from teachers to students with little emphasis on how robustly those models were derived, the uncertainties that persist around them, and how they must be recalibrated to reflect advances worthy of incorporation into practice. 

      ChatGPT passed an examination that rewards memorizing the components of a system rather than analyzing how it works, how it fails, how it was created, how it is maintained. Its success demonstrates some of the shortcomings in how we train and evaluate medical students. Critical thinking requires appreciation that ground truths in medicine continually shift, and more importantly, an understanding how and why they shift.

      Q: What steps do you think the medical community should take to modify how students are taught and evaluated?  

      A: Learning is about leveraging the current body of knowledge, understanding its gaps, and seeking to fill those gaps. It requires being comfortable with and being able to probe the uncertainties. We fail as teachers by not teaching students how to understand the gaps in the current body of knowledge. We fail them when we preach certainty over curiosity, and hubris over humility.  

      Medical education also requires being aware of the biases in the way medical knowledge is created and validated. These biases are best addressed by optimizing the cognitive diversity within the community. More than ever, there is a need to inspire cross-disciplinary collaborative learning and problem-solving. Medical students need data science skills that will allow every clinician to contribute to, continually assess, and recalibrate medical knowledge.

      Q: Do you see any upside to ChatGPT’s success in this exam? Are there beneficial ways that ChatGPT and other forms of AI can contribute to the practice of medicine? 

      A: There is no question that large language models (LLMs) such as ChatGPT are very powerful tools in sifting through content beyond the capabilities of experts, or even groups of experts, and extracting knowledge. However, we will need to address the problem of data bias before we can leverage LLMs and other artificial intelligence technologies. The body of knowledge that LLMs train on, both medical and beyond, is dominated by content and research from well-funded institutions in high-income countries. It is not representative of most of the world.

      We have also learned that even mechanistic models of health and disease may be biased. These inputs are fed to encoders and transformers that are oblivious to these biases. Ground truths in medicine are continuously shifting, and currently, there is no way to determine when ground truths have drifted. LLMs do not evaluate the quality and the bias of the content they are being trained on. Neither do they provide the level of uncertainty around their output. But the perfect should not be the enemy of the good. There is tremendous opportunity to improve the way health care providers currently make clinical decisions, which we know are tainted with unconscious bias. I have no doubt AI will deliver its promise once we have optimized the data input. More

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      in Data Management & Statistics

      Subtle biases in AI can influence emergency decisions

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      It’s no secret that people harbor biases — some unconscious, perhaps, and others painfully overt. The average person might suppose that computers — machines typically made of plastic, steel, glass, silicon, and various metals — are free of prejudice. While that assumption may hold for computer hardware, the same is not always true for computer software, which is programmed by fallible humans and can be fed data that is, itself, compromised in certain respects.

      Artificial intelligence (AI) systems — those based on machine learning, in particular — are seeing increased use in medicine for diagnosing specific diseases, for example, or evaluating X-rays. These systems are also being relied on to support decision-making in other areas of health care. Recent research has shown, however, that machine learning models can encode biases against minority subgroups, and the recommendations they make may consequently reflect those same biases.

      A new study by researchers from MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and the MIT Jameel Clinic, which was published last month in Communications Medicine, assesses the impact that discriminatory AI models can have, especially for systems that are intended to provide advice in urgent situations. “We found that the manner in which the advice is framed can have significant repercussions,” explains the paper’s lead author, Hammaad Adam, a PhD student at MIT’s Institute for Data Systems and Society. “Fortunately, the harm caused by biased models can be limited (though not necessarily eliminated) when the advice is presented in a different way.” The other co-authors of the paper are Aparna Balagopalan and Emily Alsentzer, both PhD students, and the professors Fotini Christia and Marzyeh Ghassemi.

      AI models used in medicine can suffer from inaccuracies and inconsistencies, in part because the data used to train the models are often not representative of real-world settings. Different kinds of X-ray machines, for instance, can record things differently and hence yield different results. Models trained predominately on white people, moreover, may not be as accurate when applied to other groups. The Communications Medicine paper is not focused on issues of that sort but instead addresses problems that stem from biases and on ways to mitigate the adverse consequences.

      A group of 954 people (438 clinicians and 516 nonexperts) took part in an experiment to see how AI biases can affect decision-making. The participants were presented with call summaries from a fictitious crisis hotline, each involving a male individual undergoing a mental health emergency. The summaries contained information as to whether the individual was Caucasian or African American and would also mention his religion if he happened to be Muslim. A typical call summary might describe a circumstance in which an African American man was found at home in a delirious state, indicating that “he has not consumed any drugs or alcohol, as he is a practicing Muslim.” Study participants were instructed to call the police if they thought the patient was likely to turn violent; otherwise, they were encouraged to seek medical help.

      The participants were randomly divided into a control or “baseline” group plus four other groups designed to test responses under slightly different conditions. “We want to understand how biased models can influence decisions, but we first need to understand how human biases can affect the decision-making process,” Adam notes. What they found in their analysis of the baseline group was rather surprising: “In the setting we considered, human participants did not exhibit any biases. That doesn’t mean that humans are not biased, but the way we conveyed information about a person’s race and religion, evidently, was not strong enough to elicit their biases.”

      The other four groups in the experiment were given advice that either came from a biased or unbiased model, and that advice was presented in either a “prescriptive” or a “descriptive” form. A biased model would be more likely to recommend police help in a situation involving an African American or Muslim person than would an unbiased model. Participants in the study, however, did not know which kind of model their advice came from, or even that models delivering the advice could be biased at all. Prescriptive advice spells out what a participant should do in unambiguous terms, telling them they should call the police in one instance or seek medical help in another. Descriptive advice is less direct: A flag is displayed to show that the AI system perceives a risk of violence associated with a particular call; no flag is shown if the threat of violence is deemed small.  

      A key takeaway of the experiment is that participants “were highly influenced by prescriptive recommendations from a biased AI system,” the authors wrote. But they also found that “using descriptive rather than prescriptive recommendations allowed participants to retain their original, unbiased decision-making.” In other words, the bias incorporated within an AI model can be diminished by appropriately framing the advice that’s rendered. Why the different outcomes, depending on how advice is posed? When someone is told to do something, like call the police, that leaves little room for doubt, Adam explains. However, when the situation is merely described — classified with or without the presence of a flag — “that leaves room for a participant’s own interpretation; it allows them to be more flexible and consider the situation for themselves.”

      Second, the researchers found that the language models that are typically used to offer advice are easy to bias. Language models represent a class of machine learning systems that are trained on text, such as the entire contents of Wikipedia and other web material. When these models are “fine-tuned” by relying on a much smaller subset of data for training purposes — just 2,000 sentences, as opposed to 8 million web pages — the resultant models can be readily biased.  

      Third, the MIT team discovered that decision-makers who are themselves unbiased can still be misled by the recommendations provided by biased models. Medical training (or the lack thereof) did not change responses in a discernible way. “Clinicians were influenced by biased models as much as non-experts were,” the authors stated.

      “These findings could be applicable to other settings,” Adam says, and are not necessarily restricted to health care situations. When it comes to deciding which people should receive a job interview, a biased model could be more likely to turn down Black applicants. The results could be different, however, if instead of explicitly (and prescriptively) telling an employer to “reject this applicant,” a descriptive flag is attached to the file to indicate the applicant’s “possible lack of experience.”

      The implications of this work are broader than just figuring out how to deal with individuals in the midst of mental health crises, Adam maintains.  “Our ultimate goal is to make sure that machine learning models are used in a fair, safe, and robust way.” More

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      Large language models help decipher clinical notes

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      Electronic health records (EHRs) need a new public relations manager. Ten years ago, the U.S. government passed a law that required hospitals to digitize their health records with the intent of improving and streamlining care. The enormous amount of information in these now-digital records could be used to answer very specific questions beyond the scope of clinical trials: What’s the right dose of this medication for patients with this height and weight? What about patients with a specific genomic profile?

      Unfortunately, most of the data that could answer these questions is trapped in doctor’s notes, full of jargon and abbreviations. These notes are hard for computers to understand using current techniques — extracting information requires training multiple machine learning models. Models trained for one hospital, also, don’t work well at others, and training each model requires domain experts to label lots of data, a time-consuming and expensive process. 

      An ideal system would use a single model that can extract many types of information, work well at multiple hospitals, and learn from a small amount of labeled data. But how? Researchers from MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) believed that to disentangle the data, they needed to call on something bigger: large language models. To pull that important medical information, they used a very big, GPT-3 style model to do tasks like expand overloaded jargon and acronyms and extract medication regimens. 

      For example, the system takes an input, which in this case is a clinical note, “prompts” the model with a question about the note, such as “expand this abbreviation, C-T-A.” The system returns an output such as “clear to auscultation,” as opposed to say, a CT angiography. The objective of extracting this clean data, the team says, is to eventually enable more personalized clinical recommendations. 

      Medical data is, understandably, a pretty tricky resource to navigate freely. There’s plenty of red tape around using public resources for testing the performance of large models because of data use restrictions, so the team decided to scrape together their own. Using a set of short, publicly available clinical snippets, they cobbled together a small dataset to enable evaluation of the extraction performance of large language models. 

      “It’s challenging to develop a single general-purpose clinical natural language processing system that will solve everyone’s needs and be robust to the huge variation seen across health datasets. As a result, until today, most clinical notes are not used in downstream analyses or for live decision support in electronic health records. These large language model approaches could potentially transform clinical natural language processing,” says David Sontag, MIT professor of electrical engineering and computer science, principal investigator in CSAIL and the Institute for Medical Engineering and Science, and supervising author on a paper about the work, which will be presented at the Conference on Empirical Methods in Natural Language Processing. “The research team’s advances in zero-shot clinical information extraction makes scaling possible. Even if you have hundreds of different use cases, no problem — you can build each model with a few minutes of work, versus having to label a ton of data for that particular task.”

      For example, without any labels at all, the researchers found these models could achieve 86 percent accuracy at expanding overloaded acronyms, and the team developed additional methods to boost this further to 90 percent accuracy, with still no labels required.

      Imprisoned in an EHR 

      Experts have been steadily building up large language models (LLMs) for quite some time, but they burst onto the mainstream with GPT-3’s widely covered ability to complete sentences. These LLMs are trained on a huge amount of text from the internet to finish sentences and predict the next most likely word. 

      While previous, smaller models like earlier GPT iterations or BERT have pulled off a good performance for extracting medical data, they still require substantial manual data-labeling effort. 

      For example, a note, “pt will dc vanco due to n/v” means that this patient (pt) was taking the antibiotic vancomycin (vanco) but experienced nausea and vomiting (n/v) severe enough for the care team to discontinue (dc) the medication. The team’s research avoids the status quo of training separate machine learning models for each task (extracting medication, side effects from the record, disambiguating common abbreviations, etc). In addition to expanding abbreviations, they investigated four other tasks, including if the models could parse clinical trials and extract detail-rich medication regimens.  

      “Prior work has shown that these models are sensitive to the prompt’s precise phrasing. Part of our technical contribution is a way to format the prompt so that the model gives you outputs in the correct format,” says Hunter Lang, CSAIL PhD student and author on the paper. “For these extraction problems, there are structured output spaces. The output space is not just a string. It can be a list. It can be a quote from the original input. So there’s more structure than just free text. Part of our research contribution is encouraging the model to give you an output with the correct structure. That significantly cuts down on post-processing time.”

      The approach can’t be applied to out-of-the-box health data at a hospital: that requires sending private patient information across the open internet to an LLM provider like OpenAI. The authors showed that it’s possible to work around this by distilling the model into a smaller one that could be used on-site.

      The model — sometimes just like humans — is not always beholden to the truth. Here’s what a potential problem might look like: Let’s say you’re asking the reason why someone took medication. Without proper guardrails and checks, the model might just output the most common reason for that medication, if nothing is explicitly mentioned in the note. This led to the team’s efforts to force the model to extract more quotes from data and less free text.

      Future work for the team includes extending to languages other than English, creating additional methods for quantifying uncertainty in the model, and pulling off similar results with open-sourced models. 

      “Clinical information buried in unstructured clinical notes has unique challenges compared to general domain text mostly due to large use of acronyms, and inconsistent textual patterns used across different health care facilities,” says Sadid Hasan, AI lead at Microsoft and former executive director of AI at CVS Health, who was not involved in the research. “To this end, this work sets forth an interesting paradigm of leveraging the power of general domain large language models for several important zero-/few-shot clinical NLP tasks. Specifically, the proposed guided prompt design of LLMs to generate more structured outputs could lead to further developing smaller deployable models by iteratively utilizing the model generated pseudo-labels.”

      “AI has accelerated in the last five years to the point at which these large models can predict contextualized recommendations with benefits rippling out across a variety of domains such as suggesting novel drug formulations, understanding unstructured text, code recommendations or create works of art inspired by any number of human artists or styles,” says Parminder Bhatia, who was formerly Head of Machine Learning at AWS Health AI and is currently Head of ML for low-code applications leveraging large language models at AWS AI Labs. “One of the applications of these large models [the team has] recently launched is Amazon CodeWhisperer, which is [an] ML-powered coding companion that helps developers in building applications.”

      As part of the MIT Abdul Latif Jameel Clinic for Machine Learning in Health, Agrawal, Sontag, and Lang wrote the paper alongside Yoon Kim, MIT assistant professor and CSAIL principal investigator, and Stefan Hegselmann, a visiting PhD student from the University of Muenster. First-author Agrawal’s research was supported by a Takeda Fellowship, the MIT Deshpande Center for Technological Innovation, and the MLA@CSAIL Initiatives. More