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    Making genetic prediction models more inclusive

    While any two human genomes are about 99.9 percent identical, genetic variation in the remaining 0.1 percent plays an important role in shaping human diversity, including a person’s risk for developing certain diseases.

    Measuring the cumulative effect of these small genetic differences can provide an estimate of an individual’s genetic risk for a particular disease or their likelihood of having a particular trait. However, the majority of models used to generate these “polygenic scores” are based on studies done in people of European descent, and do not accurately gauge the risk for people of non-European ancestry or people whose genomes contain a mixture of chromosome regions inherited from previously isolated populations, also known as admixed ancestry.

    In an effort to make these genetic scores more inclusive, MIT researchers have created a new model that takes into account genetic information from people from a wider diversity of genetic ancestries across the world. Using this model, they showed that they could increase the accuracy of genetics-based predictions for a variety of traits, especially for people from populations that have been traditionally underrepresented in genetic studies.

    “For people of African ancestry, our model proved to be about 60 percent more accurate on average,” says Manolis Kellis, a professor of computer science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard. “For people of admixed genetic backgrounds more broadly, who have been excluded from most previous models, the accuracy of our model increased by an average of about 18 percent.”

    The researchers hope their more inclusive modeling approach could help improve health outcomes for a wider range of people and promote health equity by spreading the benefits of genomic sequencing more widely across the globe.

    “What we have done is created a method that allows you to be much more accurate for admixed and ancestry-diverse individuals, and ensure the results and the benefits of human genetics research are equally shared by everyone,” says MIT postdoc Yosuke Tanigawa, the lead and co-corresponding author of the paper, which appears today in open-access form in the American Journal of Human Genetics. The researchers have made all of their data publicly available for the broader scientific community to use.

    More inclusive models

    The work builds on the Human Genome Project, which mapped all of the genes found in the human genome, and on subsequent large-scale, cohort-based studies of how genetic variants in the human genome are linked to disease risk and other differences between individuals.

    These studies showed that the effect of any individual genetic variant on its own is typically very small. Together, these small effects add up and influence the risk of developing heart disease or diabetes, having a stroke, or being diagnosed with psychiatric disorders such as schizophrenia.

    “We have hundreds of thousands of genetic variants that are associated with complex traits, each of which is individually playing a weak effect, but together they are beginning to be predictive for disease predispositions,” Kellis says.

    However, most of these genome-wide association studies included few people of non-European descent, so polygenic risk models based on them translate poorly to non-European populations. People from different geographic areas can have different patterns of genetic variation, shaped by stochastic drift, population history, and environmental factors — for example, in people of African descent, genetic variants that protect against malaria are more common than in other populations. Those variants also affect other traits involving the immune system, such as counts of neutrophils, a type of immune cell. That variation would not be well-captured in a model based on genetic analysis of people of European ancestry alone.

    “If you are an individual of African descent, of Latin American descent, of Asian descent, then you are currently being left out by the system,” Kellis says. “This inequity in the utilization of genetic information for predicting risk of patients can cause unnecessary burden, unnecessary deaths, and unnecessary lack of prevention, and that’s where our work comes in.”

    Some researchers have begun trying to address these disparities by creating distinct models for people of European descent, of African descent, or of Asian descent. These emerging approaches assign individuals to distinct genetic ancestry groups, aggregate the data to create an association summary, and make genetic prediction models. However, these approaches still don’t represent people of admixed genetic backgrounds well.

    “Our approach builds on the previous work without requiring researchers to assign individuals or local genomic segments of individuals to predefined distinct genetic ancestry groups,” Tanigawa says. “Instead, we develop a single model for everybody by directly working on individuals across the continuum of their genetic ancestries.”

    In creating their new model, the MIT team used computational and statistical techniques that enabled them to study each individual’s unique genetic profile instead of grouping individuals by population. This methodological advancement allowed the researchers to include people of admixed ancestry, who made up nearly 10 percent of the UK Biobank dataset used for this study and currently account for about one in seven newborns in the United States.

    “Because we work at the individual level, there is no need for computing summary-level data for different populations,” Kellis says. “Thus, we did not need to exclude individuals of admixed ancestry, increasing our power by including more individuals and representing contributions from all populations in our combined model.”

    Better predictions

    To create their new model, the researchers used genetic data from more than 280,000 people, which was collected by UK Biobank, a large-scale biomedical database and research resource containing de-identified genetic, lifestyle, and health information from half a million U.K. participants. Using another set of about 81,000 held-out individuals from the UK Biobank, the researchers evaluated their model across 60 traits, which included traits related to body size and shape, such as height and body mass index, as well as blood traits such as white blood cell count and red blood cell count, which also have a genetic basis.

    The researchers found that, compared to models trained only on European-ancestry individuals, their model’s predictions are more accurate for all genetic ancestry groups. The most notable gain was for people of African ancestry, who showed 61 percent average improvements, even though they only made up about 1.5 percent of samples in UK Biobank. The researchers also saw improvements of 11 percent for people of South Asian descent and 5 percent for white British people. Predictions for people of admixed ancestry improved by about 18 percent.

    “When you bring all the individuals together in the training set, everybody contributes to the training of the polygenic score modeling on equal footing,” Tanigawa says. “Combined with increasingly more inclusive data collection efforts, our method can help leverage these efforts to improve predictive accuracy for all.”

    The MIT team hopes its approach can eventually be incorporated into tests of an individual’s risk of a variety of diseases. Such tests could be combined with conventional risk factors and used to help doctors diagnose disease or to help people manage their risk for certain diseases before they develop.

    “Our work highlights the power of diversity, equity, and inclusion efforts in the context of genomics research,” Tanigawa says.

    The researchers now hope to add even more data to their model, including data from the United States, and to apply it to additional traits that they didn’t analyze in this study.

    “This is just the start,” Kellis says. “We can’t wait to see more people join our effort to propel inclusive human genetics research.”

    The research was funded by the National Institutes of Health. More

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    How an archeological approach can help leverage biased data in AI to improve medicine

    The classic computer science adage “garbage in, garbage out” lacks nuance when it comes to understanding biased medical data, argue computer science and bioethics professors from MIT, Johns Hopkins University, and the Alan Turing Institute in a new opinion piece published in a recent edition of the New England Journal of Medicine (NEJM). The rising popularity of artificial intelligence has brought increased scrutiny to the matter of biased AI models resulting in algorithmic discrimination, which the White House Office of Science and Technology identified as a key issue in their recent Blueprint for an AI Bill of Rights. 

    When encountering biased data, particularly for AI models used in medical settings, the typical response is to either collect more data from underrepresented groups or generate synthetic data making up for missing parts to ensure that the model performs equally well across an array of patient populations. But the authors argue that this technical approach should be augmented with a sociotechnical perspective that takes both historical and current social factors into account. By doing so, researchers can be more effective in addressing bias in public health. 

    “The three of us had been discussing the ways in which we often treat issues with data from a machine learning perspective as irritations that need to be managed with a technical solution,” recalls co-author Marzyeh Ghassemi, an assistant professor in electrical engineering and computer science and an affiliate of the Abdul Latif Jameel Clinic for Machine Learning in Health (Jameel Clinic), the Computer Science and Artificial Intelligence Laboratory (CSAIL), and Institute of Medical Engineering and Science (IMES). “We had used analogies of data as an artifact that gives a partial view of past practices, or a cracked mirror holding up a reflection. In both cases the information is perhaps not entirely accurate or favorable: Maybe we think that we behave in certain ways as a society — but when you actually look at the data, it tells a different story. We might not like what that story is, but once you unearth an understanding of the past you can move forward and take steps to address poor practices.” 

    Data as artifact 

    In the paper, titled “Considering Biased Data as Informative Artifacts in AI-Assisted Health Care,” Ghassemi, Kadija Ferryman, and Maxine Mackintosh make the case for viewing biased clinical data as “artifacts” in the same way anthropologists or archeologists would view physical objects: pieces of civilization-revealing practices, belief systems, and cultural values — in the case of the paper, specifically those that have led to existing inequities in the health care system. 

    For example, a 2019 study showed that an algorithm widely considered to be an industry standard used health-care expenditures as an indicator of need, leading to the erroneous conclusion that sicker Black patients require the same level of care as healthier white patients. What researchers found was algorithmic discrimination failing to account for unequal access to care.  

    In this instance, rather than viewing biased datasets or lack of data as problems that only require disposal or fixing, Ghassemi and her colleagues recommend the “artifacts” approach as a way to raise awareness around social and historical elements influencing how data are collected and alternative approaches to clinical AI development. 

    “If the goal of your model is deployment in a clinical setting, you should engage a bioethicist or a clinician with appropriate training reasonably early on in problem formulation,” says Ghassemi. “As computer scientists, we often don’t have a complete picture of the different social and historical factors that have gone into creating data that we’ll be using. We need expertise in discerning when models generalized from existing data may not work well for specific subgroups.” 

    When more data can actually harm performance 

    The authors acknowledge that one of the more challenging aspects of implementing an artifact-based approach is being able to assess whether data have been racially corrected: i.e., using white, male bodies as the conventional standard that other bodies are measured against. The opinion piece cites an example from the Chronic Kidney Disease Collaboration in 2021, which developed a new equation to measure kidney function because the old equation had previously been “corrected” under the blanket assumption that Black people have higher muscle mass. Ghassemi says that researchers should be prepared to investigate race-based correction as part of the research process. 

    In another recent paper accepted to this year’s International Conference on Machine Learning co-authored by Ghassemi’s PhD student Vinith Suriyakumar and University of California at San Diego Assistant Professor Berk Ustun, the researchers found that assuming the inclusion of personalized attributes like self-reported race improve the performance of ML models can actually lead to worse risk scores, models, and metrics for minority and minoritized populations.  

    “There’s no single right solution for whether or not to include self-reported race in a clinical risk score. Self-reported race is a social construct that is both a proxy for other information, and deeply proxied itself in other medical data. The solution needs to fit the evidence,” explains Ghassemi. 

    How to move forward 

    This is not to say that biased datasets should be enshrined, or biased algorithms don’t require fixing — quality training data is still key to developing safe, high-performance clinical AI models, and the NEJM piece highlights the role of the National Institutes of Health (NIH) in driving ethical practices.  

    “Generating high-quality, ethically sourced datasets is crucial for enabling the use of next-generation AI technologies that transform how we do research,” NIH acting director Lawrence Tabak stated in a press release when the NIH announced its $130 million Bridge2AI Program last year. Ghassemi agrees, pointing out that the NIH has “prioritized data collection in ethical ways that cover information we have not previously emphasized the value of in human health — such as environmental factors and social determinants. I’m very excited about their prioritization of, and strong investments towards, achieving meaningful health outcomes.” 

    Elaine Nsoesie, an associate professor at the Boston University of Public Health, believes there are many potential benefits to treating biased datasets as artifacts rather than garbage, starting with the focus on context. “Biases present in a dataset collected for lung cancer patients in a hospital in Uganda might be different from a dataset collected in the U.S. for the same patient population,” she explains. “In considering local context, we can train algorithms to better serve specific populations.” Nsoesie says that understanding the historical and contemporary factors shaping a dataset can make it easier to identify discriminatory practices that might be coded in algorithms or systems in ways that are not immediately obvious. She also notes that an artifact-based approach could lead to the development of new policies and structures ensuring that the root causes of bias in a particular dataset are eliminated. 

    “People often tell me that they are very afraid of AI, especially in health. They’ll say, ‘I’m really scared of an AI misdiagnosing me,’ or ‘I’m concerned it will treat me poorly,’” Ghassemi says. “I tell them, you shouldn’t be scared of some hypothetical AI in health tomorrow, you should be scared of what health is right now. If we take a narrow technical view of the data we extract from systems, we could naively replicate poor practices. That’s not the only option — realizing there is a problem is our first step towards a larger opportunity.”  More

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    Supporting sustainability, digital health, and the future of work

    The MIT and Accenture Convergence Initiative for Industry and Technology has selected three new research projects that will receive support from the initiative. The research projects aim to accelerate progress in meeting complex societal needs through new business convergence insights in technology and innovation.

    Established in MIT’s School of Engineering and now in its third year, the MIT and Accenture Convergence Initiative is furthering its mission to bring together technological experts from across business and academia to share insights and learn from one another. Recently, Thomas W. Malone, the Patrick J. McGovern (1959) Professor of Management, joined the initiative as its first-ever faculty lead. The research projects relate to three of the initiative’s key focus areas: sustainability, digital health, and the future of work.

    “The solutions these research teams are developing have the potential to have tremendous impact,” says Anantha Chandrakasan, dean of the School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. “They embody the initiative’s focus on advancing data-driven research that addresses technology and industry convergence.”

    “The convergence of science and technology driven by advancements in generative AI, digital twins, quantum computing, and other technologies makes this an especially exciting time for Accenture and MIT to be undertaking this joint research,” says Kenneth Munie, senior managing director at Accenture Strategy, Life Sciences. “Our three new research projects focusing on sustainability, digital health, and the future of work have the potential to help guide and shape future innovations that will benefit the way we work and live.”

    The MIT and Accenture Convergence Initiative charter project researchers are described below.

    Accelerating the journey to net zero with industrial clusters

    Jessika Trancik is a professor at the Institute for Data, Systems, and Society (IDSS). Trancik’s research examines the dynamic costs, performance, and environmental impacts of energy systems to inform climate policy and accelerate beneficial and equitable technology innovation. Trancik’s project aims to identify how industrial clusters can enable companies to derive greater value from decarbonization, potentially making companies more willing to invest in the clean energy transition.

    To meet the ambitious climate goals that have been set by countries around the world, rising greenhouse gas emissions trends must be rapidly reversed. Industrial clusters — geographically co-located or otherwise-aligned groups of companies representing one or more industries — account for a significant portion of greenhouse gas emissions globally. With major energy consumers “clustered” in proximity, industrial clusters provide a potential platform to scale low-carbon solutions by enabling the aggregation of demand and the coordinated investment in physical energy supply infrastructure.

    In addition to Trancik, the research team working on this project will include Aliza Khurram, a postdoc in IDSS; Micah Ziegler, an IDSS research scientist; Melissa Stark, global energy transition services lead at Accenture; Laura Sanderfer, strategy consulting manager at Accenture; and Maria De Miguel, strategy senior analyst at Accenture.

    Eliminating childhood obesity

    Anette “Peko” Hosoi is the Neil and Jane Pappalardo Professor of Mechanical Engineering. A common theme in her work is the fundamental study of shape, kinematic, and rheological optimization of biological systems with applications to the emergent field of soft robotics. Her project will use both data from existing studies and synthetic data to create a return-on-investment (ROI) calculator for childhood obesity interventions so that companies can identify earlier returns on their investment beyond reduced health-care costs.

    Childhood obesity is too prevalent to be solved by a single company, industry, drug, application, or program. In addition to the physical and emotional impact on children, society bears a cost through excess health care spending, lost workforce productivity, poor school performance, and increased family trauma. Meaningful solutions require multiple organizations, representing different parts of society, working together with a common understanding of the problem, the economic benefits, and the return on investment. ROI is particularly difficult to defend for any single organization because investment and return can be separated by many years and involve asymmetric investments, returns, and allocation of risk. Hosoi’s project will consider the incentives for a particular entity to invest in programs in order to reduce childhood obesity.

    Hosoi will be joined by graduate students Pragya Neupane and Rachael Kha, both of IDSS, as well a team from Accenture that includes Kenneth Munie, senior managing director at Accenture Strategy, Life Sciences; Kaveh Safavi, senior managing director in Accenture Health Industry; and Elizabeth Naik, global health and public service research lead.

    Generating innovative organizational configurations and algorithms for dealing with the problem of post-pandemic employment

    Thomas Malone is the Patrick J. McGovern (1959) Professor of Management at the MIT Sloan School of Management and the founding director of the MIT Center for Collective Intelligence. His research focuses on how new organizations can be designed to take advantage of the possibilities provided by information technology. Malone will be joined in this project by John Horton, the Richard S. Leghorn (1939) Career Development Professor at the MIT Sloan School of Management, whose research focuses on the intersection of labor economics, market design, and information systems. Malone and Horton’s project will look to reshape the future of work with the help of lessons learned in the wake of the pandemic.

    The Covid-19 pandemic has been a major disrupter of work and employment, and it is not at all obvious how governments, businesses, and other organizations should manage the transition to a desirable state of employment as the pandemic recedes. Using natural language processing algorithms such as GPT-4, this project will look to identify new ways that companies can use AI to better match applicants to necessary jobs, create new types of jobs, assess skill training needed, and identify interventions to help include women and other groups whose employment was disproportionately affected by the pandemic.

    In addition to Malone and Horton, the research team will include Rob Laubacher, associate director and research scientist at the MIT Center for Collective Intelligence, and Kathleen Kennedy, executive director at the MIT Center for Collective Intelligence and senior director at MIT Horizon. The team will also include Nitu Nivedita, managing director of artificial intelligence at Accenture, and Thomas Hancock, data science senior manager at Accenture. More

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

    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

    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

    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

    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.

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    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

    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. 

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    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