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  • Method prevents an AI model from being overconfident about wrong answers

    Method prevents an AI model from being overconfident about wrong answers

    People use large language models for a huge array of tasks, from translating an article to identifying financial fraud. However, despite the incredible capabilities and versatility of these models, they sometimes generate inaccurate responses.

    On top of that problem, the models can be overconfident about wrong answers or underconfident about correct ones, making it tough for a user to know when a model can be trusted.

    Researchers typically calibrate a machine-learning model to ensure its level of confidence lines up with its accuracy. A well-calibrated model should have less confidence about an incorrect prediction, and vice-versa. But because large language models (LLMs) can be applied to a seemingly endless collection of diverse tasks, traditional calibration methods are ineffective.

    Now, researchers from MIT and the MIT-IBM Watson AI Lab have introduced a calibration method tailored to large language models. Their method, called Thermometer, involves building a smaller, auxiliary model that runs on top of a large language model to calibrate it.

    Thermometer is more efficient than other approaches — requiring less power-hungry computation — while preserving the accuracy of the model and enabling it to produce better-calibrated responses on tasks it has not seen before.

    By enabling efficient calibration of an LLM for a variety of tasks, Thermometer could help users pinpoint situations where a model is overconfident about false predictions, ultimately preventing them from deploying that model in a situation where it may fail.

    “With Thermometer, we want to provide the user with a clear signal to tell them whether a model’s response is accurate or inaccurate, in a way that reflects the model’s uncertainty, so they know if that model is reliable,” says Maohao Shen, an electrical engineering and computer science (EECS) graduate student and lead author of a paper on Thermometer.

    Shen is joined on the paper by Gregory Wornell, the Sumitomo Professor of Engineering who leads the Signals, Information, and Algorithms Laboratory in the Research Laboratory for Electronics, and is a member of the MIT-IBM Watson AI Lab; senior author Soumya Ghosh, a research staff member in the MIT-IBM Watson AI Lab; as well as others at MIT and the MIT-IBM Watson AI Lab. The research was recently presented at the International Conference on Machine Learning.

    Universal calibration

    Since traditional machine-learning models are typically designed to perform a single task, calibrating them usually involves one task-specific method. On the other hand, since LLMs have the flexibility to perform many tasks, using a traditional method to calibrate that model for one task might hurt its performance on another task.

    Calibrating an LLM often involves sampling from the model multiple times to obtain different predictions and then aggregating these predictions to obtain better-calibrated confidence. However, because these models have billions of parameters, the computational costs of such approaches rapidly add up.

    “In a sense, large language models are universal because they can handle various tasks. So, we need a universal calibration method that can also handle many different tasks,” says Shen.

    With Thermometer, the researchers developed a versatile technique that leverages a classical calibration method called temperature scaling to efficiently calibrate an LLM for a new task.

    In this context, a “temperature” is a scaling parameter used to adjust a model’s confidence to be aligned with its prediction accuracy. Traditionally, one determines the right temperature using a labeled validation dataset of task-specific examples.

    Since LLMs are often applied to new tasks, labeled datasets can be nearly impossible to acquire. For instance, a user who wants to deploy an LLM to answer customer questions about a new product likely does not have a dataset containing such questions and answers.

    Instead of using a labeled dataset, the researchers train an auxiliary model that runs on top of an LLM to automatically predict the temperature needed to calibrate it for this new task.

    They use labeled datasets of a few representative tasks to train the Thermometer model, but then once it has been trained, it can generalize to new tasks in a similar category without the need for additional labeled data.

    A Thermometer model trained on a collection of multiple-choice question datasets, perhaps including one with algebra questions and one with medical questions, could be used to calibrate an LLM that will answer questions about geometry or biology, for instance.

    “The aspirational goal is for it to work on any task, but we are not quite there yet,” Ghosh says.

    The Thermometer model only needs to access a small part of the LLM’s inner workings to predict the right temperature that will calibrate its prediction for data points of a specific task.

    An efficient approach

    Importantly, the technique does not require multiple training runs and only slightly slows the LLM. Plus, since temperature scaling does not alter a model’s predictions, Thermometer preserves its accuracy.

    When they compared Thermometer to several baselines on multiple tasks, it consistently produced better-calibrated uncertainty measures while requiring much less computation.

    “As long as we train a Thermometer model on a sufficiently large number of tasks, it should be able to generalize well across any new task, just like a large language model, it is also a universal model,” Shen adds.

    The researchers also found that if they train a Thermometer model for a smaller LLM, it can be directly applied to calibrate a larger LLM within the same family.

    In the future, they want to adapt Thermometer for more complex text-generation tasks and apply the technique to even larger LLMs. The researchers also hope to quantify the diversity and number of labeled datasets one would need to train a Thermometer model so it can generalize to a new task.

    This research was funded, in part, by the MIT-IBM Watson AI Lab.

  • Precision oncology via artificial intelligence on cancer biopsies

    Precision oncology via artificial intelligence on cancer biopsies

    A new generation of artificial intelligence (AI) tools designed to allow rapid, low-cost detection of clinically actionable genomic alterations directly from tumor biopsy slides has been developed by a team led by engineers and medical researchers at University of California San Diego.

    A paper describing the new AI protocol for examining routine biopsies, called DeepHRD, was recently published in the Journal of Clinical Oncology.

    Senior author Ludmil Alexandrov, Ph.D., professor of bioengineering and professor of cellular and molecular medicine at UC San Diego, says the new method is designed to save weeks and thousands of dollars from clinical oncology treatment workflows for breast and ovarian cancers.

    The team says their work represents an enormous step forward in the global efforts to eliminate the delays and health inequalities that have confounded the promise of precision medicine for cancer patients. Big picture: To develop new AI tools that can complement or replace the expensive and time-consuming genomic testing required to determine the best first-line cancer treatment specific for each individual patient.

    “A cancer patient today can expect to wait crucial weeks after their initial tumor diagnosis for a standard genomic test, resulting in life-threatening delays in treatment,” said Alexandrov. “It is very concerning that high costs and time delays render lifesaving treatment protocols inaccessible for most patients, disproportionately impacting resource-constrained settings.”

    At UC San Diego, this work represents a collaboration spanning all across campus, including the Department of Cellular and Molecular Medicine in the UC San Diego School of Medicine, the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering, Institute of Engineering in Medicine, Department of Medicine, and the UC San Diego Moores Cancer Center.

    It was the potential of precision oncology to tailor an individual patient’s treatment options that motivated the collaborators, said Erik Bergstrom, Ph.D., lead author of the study and a postdoctoral researcher in Alexandrov’s lab, which bridges bioengineering and medicine.

    “Unfortunately, high costs, tissue requirements and slow turnaround times have hindered the widespread use of precision oncology, leading to suboptimal — potentially detrimental — treatment for cancer patients,” Bergstrom said. “We wanted to see if we could develop a completely different approach to resolve this serious issue by designing AI to circumvent the need for genomic testing.”

    Bergstrom said the collaborators focused on leveraging the minimum amount of patient information that is available early in the diagnostic process. He explained that virtually every cancer patient undergoes a tumor biopsy, a tissue sample that is routinely processed and examined through a light microscope. The process was developed in the late 19th century and is still the standard backbone of early clinical oncology workflows today.

    “Our AI, applied directly to a traditional tissue slide, allows accurate, instantaneous detection of cancer genomic biomarkers,” Bergstrom said. He explained that the team focused on AI identification of a specific biomarker for homologous recombination deficiency (HRD), a condition in which a cancerous cell loses a specific DNA damage repair mechanism.

    Bergstrom pointed out that patients with ovarian or breast cancers harboring HRD generally respond well to platinum and PARP (poly-ADP ribose polymerase) therapies, two common forms of chemotherapy.

    “This AI approach saves the patient critical time,” Alexandrov added. “Oncologists can prescribe treatment immediately after initial tissue diagnosis. Remarkably, the AI test has a negligible failure rate, while current genomic tests have a failure rate of 20 to 30 percent, necessitating re-testing, or even invasive re-biopsy.”

    The study’s co-senior author Scott Lippman, M.D., UC San Diego distinguished professor of medicine, Center for Engineering and Cancer, and Moores Cancer Center member, said the new technology will remove barriers of time and money to allow immediate, universal access and equality to actionable genomic biomarker detection — required for precision therapy — for people with advanced cancers. The extraordinary aspect of this breakthrough AI, is that it will benefit highly-informed, -resourced populations, and remarkably, will close the severe disparities ‘gap’ in precision medicine, especially in resource-constrained, remote regions worldwide where testing is not yet extant.

    “The era of precision oncology took off in the late 90s, but recent U.S. studies show that the vast majority of cancer patients are not getting FDA-approved precision therapy,” Lippman said. “And the prime reason is because they’re not getting tested. As a clinical oncologist — and I’ve been doing this for nearly 40 years — there is no question that this approach is the future of precision oncology.”

    The AI technology behind DeepHRD is protected by provisional patents through UC San Diego, which have been licensed to io9, a company with strong involvement by Alexandrov, Bergstrom and Lippman, and the goal to move this AI platform into the clinical arena as quickly as possible to make precision therapy real for patients with cancer by getting them onto the precise treatments they need faster. The authors expect that the same technology could be applied to most other genomic biomarkers and many forms of cancer.

    Affiliations: The authors have the affiliations noted above: Ludmil B. Alexandrov has appointments at UC San Diego Moores Cancer Center, School of Medicine Department of Cellular and Molecular Medicine, Sanford Stem Cell Institute and the Department of Bioengineering at the Irwin & Joan Jacobs School of Engineering. Erik N. Bergstrom is affiliated with Moores Cancer Center and Department of Cellular and Molecular Medicine. Scott M. Lippman has appointments at Moores Cancer Center, Department of Medicine; and is a Member & Board of Advisors and Co-director of the Center for Engineering and Cancer, Institute of Engineering in Medicine. Other co-authors are Ammal Abbasi and Marcos Díaz-Gay, both of Moores Cancer Center and Department of Cellular and Molecular Medicine and the Jacobs School of Engineering Department of Bioengineering; Loïck Galland and Sylvain Ladoire, both of the Department of Medical Oncology and the Platform of Transfer in Biological Oncology Centre, Georges-François Leclerc Cancer Center and University of Burgundy-Franche, France.

    Funding: This work was funded by U.S. National Institutes of Health grants R01ES032547 and U01DE033345 to Ludmil B. Alexandrov, and P30 CA023100 to Scott M. Lippman, as well as by a Curebound Targeted grant and UC San Diego start-up funding to Alexandrov. The research in this study was also supported by UC San Diego Sanford Stem Cell Institute.

  • A tool for visualizing single-cell data

    A tool for visualizing single-cell data

    Modern cutting-edge research generates enormous amounts of data, presenting scientists with the challenge of visualizing and analyzing it. Researchers at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg and the Technical University of Applied Sciences Würzburg-Schweinfurt (THWS) have developed a tool for visualizing large data sets. The sCIRCLE tool allows users to explore single-cell analysis data in an interactive and user-friendly way. Their results have been published in the journal NAR Genomics and Bioinformatics.

    Antibiotic resistance is rising worldwide and poses a major challenge to healthcare systems. Understanding the underlying processes of how and why some bacteria develop such defenses is critical. Differences in bacterial gene expression — in which the information in a gene is read — could provide clues. Bacterial single-cell RNA sequencing, or “scRNA-seq,” has become an essential tool for analyzing these variations. This technology provides a detailed picture of gene expression in a single cell at a specific point in time. However, the method generates huge amounts of data that are difficult for researchers to visualize and analyze. Accordingly, there is a great need for new approaches and tools to display and understand this information.

    Researchers at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, a site of the Helmholtz Centre for Infection Research (HZI) in Braunschweig in cooperation with the Julius-Maximilians-Universität Würzburg (JMU), and designers at the Technical University of Applied Sciences Würzburg-Schweinfurt (THWS) have now developed such a tool. Their desktop application, called sCIRCLE (single-Cell Interactive Real-time Computer visualization for Low-dimensional Exploration), enables interactive 3D visualization of scRNA-seq data. It allows users to view single cells, enriched with metadata, from different angles and in real-time. A variety of filters and settings can be used to explore which genes have been expressed in particular cells at specific points in time. This capability allows researchers to focus on specific cell populations or genes of interest. “sCIRCLE is also a valuable communication tool for collaboratively examining data sets or presenting results,” says Lars Barquist. Barquist, a computational biologist who initiated the study, leads a research group at the Helmholtz Institute Würzburg. Barquist is also a professor at the University of Toronto in Canada. Additionally, sCIRCLE is already compatible with virtual reality devices, marking a step towards immersive 3D data visualization and interaction.

    A future-oriented cross-disciplinary collaboration

    The user-friendliness of sCIRCLE is notable: “The interface is easy to use and intuitively designed. sCIRCLE is therefore particularly helpful for biologists without extensive knowledge of bioinformatics,” adds Barquist. The designers and bioinformaticians worked together to make the data as simple and visually appealing as possible: “Collaboration between the disciplines of bioinformatics and design is extremely important as our data sets continue to grow and we need new ways to make them understandable,” says Barquist.

    To realize the project, THWS Master’s student Maximilian Seeger spent some time in the HIRI research group. There, he had the opportunity to work directly with the scientists. “This allowed me to understand what they wanted to explore in their data and develop an interface that would make this possible,” reports Maximilian Seeger. In test runs with data collected by HIRI researchers from different groups, the scientists tried out the tool and provided feedback. The research team has published the results in the journal NAR Genomics and Bioinformatics.

    “The joint development of sCIRCLE shows the importance of interdisciplinary and cross-institutional cooperation. I am very pleased we successfully combined the expertise of two Würzburg-based institutions in this project and look forward to future collaborations,” says Erich Schöls, professor for interactive media at THWS, who supervised Max Seeger together with Lars Barquist. “This is hopefully just the first step towards developing intuitive, interactive tools for data analysis,” says Barquist optimistically. “We will build on this foundation to make our tools even more immersive and user-friendly.” While this application currently offers only basic virtual reality integration, the team plans to create additional easy-to-use virtual spaces for data exploration in the future.

  • Genetic diagnostics of ultra-rare diseases

    Genetic diagnostics of ultra-rare diseases

    The majority of rare diseases have a genetic cause. The underlying genetic alteration can be found more and more easily, for example by means of exome sequencing (ES), leading to a molecular genetic diagnosis. ES is an examination of all sections of our genetic material (DNA) that code for proteins. As part of a Germany-wide multicenter study, ES data was collected from 1,577 patients and systematically evaluated. This made it possible to diagnose a total of 499 patients, with 34 patients showing new, previously unknown genetic diseases. The study thus makes a significant contribution to the initial description of new diseases. In addition, software based on the use of artificial intelligence (AI) was used for the first time on a broad scale to support clinical diagnosis. The “GestaltMatcher” AI system can assist in the assessment of facial features with regard to the classification of congenital genetic syndromes. The results of the study, in which 16 university locations were involved, have now been published in the journal Nature Genetics.

    Ultra-rare diseases require both multidisciplinary clinical expertise and comprehensive genetic diagnostics for optimal care. The three-year TRANSLATE NAMSE innovation fund project began at the end of 2017 with the aim of improving the care of those affected by means of modern diagnostic concepts. Researchers from 16 university hospitals analyzed the ES data of 1,577 patients, including 1,309 children, who presented to rare disease centers as part of TRANSLATE NAMSE. The aim of the project was to find the cause of the disease in as many patients as possible using innovative examination methods. A genetic cause of the rare disease was identified in 499 patients, 425 of whom were children. In total, the researchers found changes in 370 different genes. “We are particularly proud of the discovery of 34 new molecular diseases, which is a great example of knowledge-generating patient care at university hospitals,” says Dr. Theresa Brunet, one of the lead authors from the Institute of Human Genetics at the Klinikum rechts der Isar of the Technical University of Munich.

    What happens next with the unsolved cases?

    “We will examine the affected patients for whom we have not yet been able to find a diagnosis as part of the model project Genome Sequencing, or MVGenomSeq for short,” says Dr. Tobias Haack, Deputy Director of the Institute of Medical Genetics and Applied Genomics at the University Hospital of Tübingen. The MVGenomSeq builds on the success of the TRANSLATE NAMSE project and enables the analysis of clinical genomes at university hospitals throughout Germany. Unsolved cases can also be investigated in follow-up studies using new examination methods, such as long-read sequencing, which allows much longer DNA fragments to be analyzed. “Long-read sequencing enables us to find genetic changes that are difficult to detect and we assume that we will be able to make further diagnoses using this method,” says Dr. Nadja Ehmke, Head of Genome Diagnostics at Charité’s Institute of Medical Genetics and Human Genetics and one of the last authors.

    As part of the TRANSLATE NAMSE project, standardized procedures for extended genetic diagnostics for suspected rare diseases were also established at the participating rare disease centers, based on interdisciplinary case conferences. These were incorporated into standard care after the project was completed. “The interdisciplinary case conferences play an important role for those affected. This enables a comprehensive clinical characterization, which is relevant for the phenotype-based evaluation of the genetic data. In addition, the detected variants can be discussed in an interdisciplinary context,” says Dr. Magdalena Danyel, one of the first authors, who works as a specialist at the Institute of Medical Genetics and Human Genetics and a fellow of the Clinician Scientist Program of the Berlin Institute of Health (BIH) at Charité — Universitätsmedizin.

    Rare genetic diseases can sometimes be recognized by the face

    The researchers also investigated whether the supplementary use of machine learning and artificial intelligence (AI) tools improves diagnostic effectiveness and efficiency. To this end, the “GestaltMatcher” software developed by researchers in Bonn, which uses computer-assisted facial analysis to support the person using it in the diagnosis of rare diseases, was tested on a broad scale for the first time. The study used the sequence and image data of 224 people who had also consented to the computer-assisted analysis of their facial images, and it was shown that the AI-supported technology provides a clinical benefit.

    The GestaltMatcher AI can recognize abnormalities in the face and assign them to specific diseases. An important question when assessing genetic data is: Does the phenotype match the genotype? The AI can provide support here. “GestaltMatcher is like an expert opinion that we can provide to any medical professional in a matter of seconds. Early diagnosis is essential for those affected by rare diseases and their families. Supportive use of the software by pediatricians could already be useful in the case of abnormalities during the U7 screening at 21 to 24 months or U7a at 34 to 36 months,” says corresponding author Prof. Peter Krawitz, Director of the Institute for Genomic Statistics and Bioinformatics (IGSB) at the University Hospital Bonn (UKB), where the GestaltMatcher AI is being developed. Prof. Krawitz is also a member of the Cluster of Excellence ImmunoSensation2 and in the Transdisciplinary Research Areas (TRA) “Modeling” and “Life & Health” at the University of Bonn. The software and app can be made available to all doctors through the non-profit organization Arbeitsgemeinschaft für Gen-Diagnostik e.V. (AGD).

    Participating institutions

    In addition to the University Hospital Bonn (UKB) and the University of Bonn, the Charité-Universitätsmedizin Berlin, Klinikum rechts der Isar of the Technical University of Munich (TUM), University Hospital Düsseldorf, Ruhr University Bochum, University Hospital Dresden, University Hospital Essen, University Hospital Halle, University Hospital Hamburg Eppendorf, University Hospital Heidelberg, University Hospital Schleswig Holstein, LMU Hospital Munich, University Hospital RWTH Aachen, University Hospital Leipzig, University Hospital Tübingen and Stellenbosch University, Cape Town, South Africa were also involved

  • Using AI to scrutinize, validate theories on animal evolution

    Using AI to scrutinize, validate theories on animal evolution

    By harnessing the power of machine learning, researchers have constructed a framework for analyzing what factors most significantly contribute to a species’ genetic diversity.

    The study, recently published in the journal Molecular Phylogenetics and Evolution, suggests that the genetic variation of two species, the Brazilian sibilator frog and the granular toad, both amphibians native to northeastern Brazil, were shaped by different processes.

    Results showed that the genetic variation in the sibilator frog was shaped mostly by population demographic events in response to habitat changes that occurred over the last 100,000 years. In contrast, genetic diversity in the granular toad was mostly shaped by contemporary landscape factors — toads that are relatively more isolated, either by geographic distance or inhospitable habitat, were more likely to be genetically different.

    While previous investigations have explored the effects of historical demographic and landscape factors on genetic diversity of these amphibians, they were conducted with separate sets of data for these factors, making it difficult to discern which was the most important. Now, researchers involved with this paper are the first to use artificial intelligence to consider how both processes shape genetic diversity equally, rather than making manual assumptions about which may have been more vital.

    “Prior to this work, we had to ask questions independently because you couldn’t investigate both influences in the same framework,” said Bryan Carstens, co-author of the study and a professor in evolution, ecology and organismal biology at The Ohio State University. “What AI allows us to do is to simulate processes that are both happening ecologically in the present and during deep-time evolutionary events and compare those findings to the actual data that we collect from these frogs.”

    Due to the sheer amount of data that’s become available to geneticists and other wildlife biologists over the past few decades, it can be challenging for researchers to identify specific factors that might be important in certain experiments, said Carstens. But by integrating large swaths of information into simulations that can account for those elements in a single analysis, it’s possible to get a much more complete chronicle of a species’ development.

    “It takes a long time to build and train our AI models, but we wanted one l that could capture the range of potential variation in the species’ histories in a way that was as faithful as we could be to what we knew about the biology of the system,” said Carstens.

    For example, while the species this study investigated dwell in the same region, there are many differences in their natural histories. Despite both their eggs and larvae being fully aquatic, the sibulator frog reproduces continuously throughout the wet season and in underground chambers, while the granular toad’s reproductive events happen explosively because they are dependent on heavy rainfall.

    Combined with their machine learning approach, the researchers’ simulation determined their model scenarios were 100% supported regarding historical explanations for the sibilator frog’s expansion, and over 99% supported for those of the granular toad.

    One of the reasons their model is so accurate is due to its ability to account for recent demographic events, including measuring how events like human development or habitat change may have affected animal genetic diversity over a long period of time.

    But even when using AI, researchers have to be careful to avoid deceptive patterns in their results, said Carstens.

    “No analysis that we do is going to capture every single factor that has been important to these species over millions of years,” he said. “So we have to allow for a range of possibilities without making it so broad that essentially any model would be able to fit the data.”

    That said, as technological strides allow researchers to answer niche ecological questions and test new hypotheses, their work is a precursor to creating an upgraded machine learning framework that could be applied to unique investigations of other species, said Carstens.

    “We’re likely to continue using different combinations of these AI tools in different ways to try to understand evolutionary history,” said Carstens. “And as we keep learning, the tools we’re using will change, and they’ll evolve to be even better.”

    Emanuel M. Fonseca, who earned his doctorate from Ohio State in 2022, was a co-author. The study was supported by the Ohio Supercomputer Center, the U.S. National Science Foundation and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior in Brazil.

  • Chatbot Iris offers students individual support

    Chatbot Iris offers students individual support

    How can a chatbot support students in lectures and with assigned exercises? Researchers at the Technical University of Munich (TUM) have developed the chatbot Iris, which offers computer science students personalized assistance with programming assignments. A study has now confirmed the chatbot’s success: Iris improves the understanding of programming concepts and represents a valuable complement to human tutors.

    A packed auditorium with over 1000 students. This is not a rare sight in introductory informatics lectures. To meet the needs of each individual student under these conditions, Stephan Krusche, professor of Software Engineering, and his team have been building the Artemis learning platform since 2016. It resembles well-known learning platforms, but offers more possibilities. For example, students not only receive their assignments through the platform, but also get immediate feedback when they make mistakes or show an incomplete understanding of concepts.

    Chatbot Iris: excellent tutor

    In October of last year, Stephan Krusche’s team at the TUM Centre for Educational Technologies added the chatbot to the platform. Iris is based on the GPT large language model of OpenAI. It is intended to help students with assigned problems, with the support geared to their individual needs. To adapt the system to the learning context, the chatbot operates as a so-called excellent tutor. That means that, rather than immediately suggesting the right solution or specific steps, Iris offers subtle hints or asks leading questions. This approach encourages students to think for themselves. To boost learning efficiency, the chatbot only answers questions directly relevant to the learning content.

    “To test the success of Iris, we surveyed over 200 students from three introductory informatics lectures,” says Patrick Bassner, a doctoral candidate at the Chair of Software Engineering. “The goal was to arrive at conclusions on how students rate the effectiveness of the support from Iris, whether students are more comfortable asking a chatbot questions than a human tutor and whether students subjectively trust Iris.”

    Iris promotes learning and students’ independence

    The responses show that the students value Iris as a valuable support, but also that a large share of those surveyed still rely on human tutors. The chatbot understands questions well and students feel comfortable and safe when using it. Iris gives them the feeling that the chats will remain private and that they are not being judged when asking questions. Especially in large lectures, this saves students from having to overcome their inhibitions to ask questions in front of the class. When studying for exams, the use of Iris is becoming commonplace. However, students feel confident enough to solve problems on exams without the support of the chatbot.

    “The integration of Iris into Artemis has shown that AI-controlled tutors can play a valuable role in university teaching,” says Stephan Krusche. “They offer personalized support that benefits learning and boosts students’ ability to help themselves.”

    The researchers plan to further optimize the chatbot Iris and want to see it being used in other subject areas.

  • Prying open the AI black box

    Prying open the AI black box

    Artificial intelligence continues to squirm its way into many aspects of our lives. But what about biology, the study of life itself? AI can sift through hundreds of thousands of genome data points to identify potential new therapeutic targets. While these genomic insights may appear helpful, scientists aren’t sure how today’s AI models come to their conclusions in the first place. Now, a new system named SQUID arrives on the scene armed to pry open AI’s black box of murky internal logic.

    SQUID, short for Surrogate Quantitative Interpretability for Deepnets, is a computational tool created by Cold Spring Harbor Laboratory (CSHL) scientists. It’s designed to help interpret how AI models analyze the genome. Compared with other analysis tools, SQUID is more consistent, reduces background noise, and can lead to more accurate predictions about the effects of genetic mutations.

    How does it work so much better? The key, CSHL Assistant Professor Peter Koo says, lies in SQUID’s specialized training.

    “The tools that people use to try to understand these models have been largely coming from other fields like computer vision or natural language processing. While they can be useful, they’re not optimal for genomics. What we did with SQUID was leverage decades of quantitative genetics knowledge to help us understand what these deep neural networks are learning,” explains Koo.

    SQUID works by first generating a library of over 100,000 variant DNA sequences. It then analyzes the library of mutations and their effects using a program called MAVE-NN (Multiplex Assays of Variant Effects Neural Network). This tool allows scientists to perform thousands of virtual experiments simultaneously. In effect, they can “fish out” the algorithms behind a given AI’s most accurate predictions. Their computational “catch” could set the stage for experiments that are more grounded in reality.

    “In silico [virtual] experiments are no replacement for actual laboratory experiments. Nevertheless, they can be very informative. They can help scientists form hypotheses for how a particular region of the genome works or how a mutation might have a clinically relevant effect,” explains CSHL Associate Professor Justin Kinney, a co-author of the study.

    There are tons of AI models in the sea. More enter the waters each day. Koo, Kinney, and colleagues hope that SQUID will help scientists grab hold of those that best meet their specialized needs.

    Though mapped, the human genome remains an incredibly challenging terrain. SQUID could help biologists navigate the field more effectively, bringing them closer to their findings’ true medical implications.

  • Scientists preserve DNA in an amber-like polymer

    Scientists preserve DNA in an amber-like polymer

    In the movie “Jurassic Park,” scientists extracted DNA that had been preserved in amber for millions of years, and used it to create a population of long-extinct dinosaurs.

    Inspired partly by that film, MIT researchers have developed a glassy, amber-like polymer that can be used for long-term storage of DNA, whether entire human genomes or digital files such as photos.

    Most current methods for storing DNA require freezing temperatures, so they consume a great deal of energy and are not feasible in many parts of the world. In contrast, the new amber-like polymer can store DNA at room temperature while protecting the molecules from damage caused by heat or water.

    The researchers showed that they could use this polymer to store DNA sequences encoding the theme music from Jurassic Park, as well as an entire human genome. They also demonstrated that the DNA can be easily removed from the polymer without damaging it.

    “Freezing DNA is the number one way to preserve it, but it’s very expensive, and it’s not scalable,” says James Banal, a former MIT postdoc. “I think our new preservation method is going to be a technology that may drive the future of storing digital information on DNA.”

    Banal and Jeremiah Johnson, the A. Thomas Geurtin Professor of Chemistry at MIT, are the senior authors of the study, published in the Journal of the American Chemical Society. Former MIT postdoc Elizabeth Prince and MIT postdoc Ho Fung Cheng are the lead authors of the paper.

    Capturing DNA

    DNA, a very stable molecule, is well-suited for storing massive amounts of information, including digital data. Digital storage systems encode text, photos, and other kind of information as a series of 0s and 1s. This same information can be encoded in DNA using the four nucleotides that make up the genetic code: A, T, G, and C. For example, G and C could be used to represent 0 while A and T represent 1.

    DNA offers a way to store this digital information at very high density: In theory, a coffee mug full of DNA could store all of the world’s data. DNA is also very stable and relatively easy to synthesize and sequence.

    In 2021, Banal and his postdoc advisor, Mark Bathe, an MIT professor of biological engineering, developed a way to store DNA in particles of silica, which could be labeled with tags that revealed the particles’ contents. That work led to a spinout called Cache DNA.

    One downside to that storage system is that it takes several days to embed DNA into the silica particles. Furthermore, removing the DNA from the particles requires hydrofluoric acid, which can be hazardous to workers handling the DNA.

    To come up with alternative storage materials, Banal began working with Johnson and members of his lab. Their idea was to use a type of polymer known as a degradable thermoset, which consists of polymers that form a solid when heated. The material also includes cleavable links that can be easily broken, allowing the polymer to be degraded in a controlled way.

    “With these deconstructable thermosets, depending on what cleavable bonds we put into them, we can choose how we want to degrade them,” Johnson says.

    For this project, the researchers decided to make their thermoset polymer from styrene and a cross-linker, which together form an amber-like thermoset called cross-linked polystyrene. This thermoset is also very hydrophobic, so it can prevent moisture from getting in and damaging the DNA. To make the thermoset degradable, the styrene monomers and cross-linkers are copolymerized with monomers called thionolactones. These links can be broken by treating them with a molecule called cysteamine.

    Because styrene is so hydrophobic, the researchers had to come up with a way to entice DNA — a hydrophilic, negatively charged molecule — into the styrene.

    To do that, they identified a combination of three monomers that they could turn into polymers that dissolve DNA by helping it interact with styrene. Each of the monomers has different features that cooperate to get the DNA out of water and into the styrene. There, the DNA forms spherical complexes, with charged DNA in the center and hydrophobic groups forming an outer layer that interacts with styrene. When heated, this solution becomes a solid glass-like block, embedded with DNA complexes.

    The researchers dubbed their method T-REX (Thermoset-REinforced Xeropreservation). The process of embedding DNA into the polymer network takes a few hours, but that could become shorter with further optimization, the researchers say.

    To release the DNA, the researchers first add cysteamine, which cleaves the bonds holding the polystyrene thermoset together, breaking it into smaller pieces. Then, a detergent called SDS can be added to remove the DNA from polystyrene without damaging it.

    Storing information

    Using these polymers, the researchers showed that they could encapsulate DNA of varying length, from tens of nucleotides up to an entire human genome (more than 50,000 base pairs). They were able to store DNA encoding the Emancipation Proclamation and the MIT logo, in addition to the theme music from “Jurassic Park.”

    After storing the DNA and then removing it, the researchers sequenced it and found that no errors had been introduced, which is a critical feature of any digital data storage system.

    The researchers also showed that the thermoset polymer can protect DNA from temperatures up to 75 degrees Celsius (167 degrees Fahrenheit). They are now working on ways to streamline the process of making the polymers and forming them into capsules for long-term storage.

    Cache DNA, a company started by Banal and Bathe, with Johnson as a member of the scientific advisory board, is now working on further developing DNA storage technology. The earliest application they envision is storing genomes for personalized medicine, and they also anticipate that these stored genomes could undergo further analysis as better technology is developed in the future.

    “The idea is, why don’t we preserve the master record of life forever?” Banal says. “Ten years or 20 years from now, when technology has advanced way more than we could ever imagine today, we could learn more and more things. We’re still in the very infancy of understanding the genome and how it relates to disease.”

    The research was funded by the National Science Foundation.

  • ‘Self-taught’ AI tool helps to diagnose and predict severity of common lung cancer

    ‘Self-taught’ AI tool helps to diagnose and predict severity of common lung cancer

    A computer program based on data from nearly a half-million tissue images and powered by artificial intelligence can accurately diagnose cases of adenocarcinoma, the most common form of lung cancer, a new study shows.

    Researchers at NYU Langone Health’s Perlmutter Cancer Center and the University of Glasgow developed and tested the program. They say that because it incorporates structural features of tumors from 452 adenocarcinoma patients, who are among the more than 11,000 patients in the United States National Cancer Institute’s Cancer Genome Atlas, the program offers an unbiased, detailed, and reliable second opinion for patients and oncologists about the presence of the cancer and the likelihood and timing of its return (prognosis).

    The research team also points out that the program is independent and “self-taught,” meaning that it determined on its own which structural features were statistically most significant to gauging the severity of disease and had the greatest impact on tumor recurrence.

    Publishing in the journal Nature Communications online June 11, the study program, also called an algorithm, or specifically, histomorphological phenotype learning (HPL), was found to accurately distinguish between similar lung cancers, adenocarcinoma and squamous cell cancers, 99% of the time. The HPL program was also found to be 72% accurate at predicting the likelihood and timing of cancer’s return after therapy, bettering the 64% accuracy in the predictions made by pathologists who directly examined the same patients’ tumor images, researchers say.

    “Our new histomorphological phenotype learning program has the potential to offer cancer specialists and their patients a quick and unbiased diagnostic tool for lung adenocarcinoma that, once further testing is complete, can also be used to help validate and even guide their treatment decisions,” said study lead investigator Nicolas Coudray, PhD, a bioinformatics programmer at NYU Grossman School of Medicine and Perlmutter Cancer Center.

    “Patients, physicians, and researchers know they can rely on this predictive modeling because it is self-taught, provides explainable decisions, and is based only on the knowledge drawn specifically from each patient’s tissue, including such features as its proportion of dying cells, tumor-fighting immune cells, and how densely packed the tumor cells are, among other features,” said Coudray.

    “Lung tissue samples can now be analyzed in minutes by our computer program to provide fairly accurate predictions of whether their cancer will return, predictions that are better than current standards of care for making a prognosis in lung adenocarcinoma,” said study co-senior investigator Aristotelis Tsirigos, PhD. Tsirigos is a professor in the Departments of Pathology and Medicine at NYU Grossman School of Medicine and Perlmutter Cancer Center, where he also serves as co-director of precision medicine and director of its Applied Bioinformatics Laboratories.

    Tsirigos says that thanks to such tools and other advances in the lung cancer biology, pathologists will be examining tissue scans on their computer screens, and less and less on microscopes, and then using their AI program to analyze the image and produce its own image of the scan. The new image, or “landscape,” they add, will offer a detailed breakdown of the tissue’s content. It might note, for example, that there is 5% necrosis and 10% tumor infiltration and what that means in terms of survival. That reading may statistically equate to an 80% chance of remaining cancer-free for two years or more, based on information from all the patient data in the program.

    To develop the HPL program, the researchers first analyzed lung adenocarcinoma tissue slides from the Cancer Genome Atlas. Adenocarcinoma was chosen for the test model because the disease is known for characteristic features. As an example, they note that its tumor cells tend to group in so-called acinar, or saclike patterns and spread predictably along the surface lining of lung cells.

    From their analysis of the slides, whose visual images were digitally scanned and broken into 432,231 small quadrants or tiles, researchers found 46 key characteristics, what they term histomorphological phenotype clusters, from both normal and diseased tissue, a subset of which were statistically linked to either cancer’s early return or to long-term survival. The findings were then confirmed by further and separate testing on tissue images from 276 men and women who were treated for adenocarcinoma at NYU Langone from 2006 to 2021.

    Researchers say their goal is to use the HPL algorithm to assign to each patient a score between 0 and 1 that reflects their statistical chance of survival and tumor recurrence for up to five years. Because the program is self-learning, they stress HPL will become increasingly more accurate as more data is added over time. To build public trust, researchers have posted their programming code online and have plans to make the new HPL tool freely available upon completion of further testing.

    Characteristics linked to tumors recurring included high tile percentages of dead cancer cells and tumor-fighting immune cells called lymphocytes, and the dense clustering of tumor cells in the outer linings of the lungs. Features tied to increased likelihood for survival were high percentages of unchanged or preserved lung sac tissue, and lack of or mild presence of inflammatory cells.

    Tsirigos says the team next plans to look at developing HPL-like programs for other cancers, such as breast, ovarian, and colorectal, that are similarly based on distinctive and key morphological features and additional molecular data. The team also has plans to expand and improve the accuracy of the current adenocarcinoma HPL program by including other data from hospital electronic health records about other illnesses and diseases, or even income and home ZIP code.

    Funding support for the new study was provided by National Institutes of Health grant P30CA016087, United Kingdom Research Council grants Ep/R018634/1 and BB/V016067/1, and European Union Horizon 2020 grant no. 101016851.

    Besides Tsirigos and Coudray, other NYU Langone researchers involved in this study are Anna Yeaton, Bojing Liu, Hortense Le, Luis Chiriboga, Afreen Karimkhan, Navneet Natula, Christopher Park, Harvey Pass, and Andre Moreira. Study co-lead investigator Adalberto Claudio Quiros, study co-investigators Xinyu Yang and John Le Quesne, and study co-senior investigator Ke Yuan are all at the University of Glasgow, UK. Study co-investigator David Moore is at the University College London, UK.

  • Artificial intelligence blood test provides a reliable way to identify lung cancer

    Artificial intelligence blood test provides a reliable way to identify lung cancer

    Using artificial intelligence technology to identify patterns of DNA fragments associated with lung cancer, researchers from the Johns Hopkins Kimmel Cancer Center and other institutions have developed and validated a liquid biopsy that may help identify lung cancer earlier.

    In a prospective study published June 3 in Cancer Discovery, the team demonstrated that artificial intelligence technology could identify people more likely to have lung cancer based on DNA fragment patterns in the blood. The study enrolled about 1,000 participants with and without cancer who met the criteria for traditional lung cancer screening with low-dose computed tomography (CT). Individuals were recruited to participate at 47 centers in 23 U.S. states. By helping to identify patients most at risk and who would benefit from follow-up CT screening, this new blood test could potentially boost lung cancer screening and reduce death rates, according to computer modeling by the team.

    “We have a simple blood test that could be done in a doctor’s office that would tell patients whether they have potential signs of lung cancer and should get a follow-up CT scan,” says the study’s corresponding author, Victor E. Velculescu, M.D., Ph.D., professor of oncology and co-director of the Cancer Genetics and Epigenetics program at the Johns Hopkins Kimmel Cancer Center.Lung cancer is the deadliest cancer in the United States, according to the National Cancer Institute, and worldwide, according to the World Health Organization. Yearly screening with CT scans in high-risk patients can help detect lung cancers early, when they are most treatable, and help avert lung cancer deaths. Screening is recommended by the U.S. Preventive Services Task Force for 15 million people nationally who are between ages 50 and 80 and have a smoking history, yet only about 6%-10% of eligible individuals are screened each year. People may be reticent to follow through on screening, Velculescu explains, due to the time it takes to arrange and go to an appointment, and the low doses of radiation they are exposed to from the scan.

    To help overcome some of these hurdles, Velculescu and his colleagues developed a test over the past five years that uses artificial intelligence to detect patterns of DNA fragments found in patients with lung cancer. It takes advantage of differences in how DNA is packaged in normal and cancer cells. DNA is neatly and consistently folded up in healthy cells, almost like a rolled-up ball of yarn, but DNA in cancer cells is more disorganized. When both types of cells die, fragments of DNA end up in the blood. The DNA fragments in patients with cancer tend to be more chaotic and irregular than the DNA fragments found in individuals who do not have cancer.

    The team trained artificial intelligence software to identify the specific patterns of DNA fragments seen in the blood of 576 people with or without lung cancer. Then, they verified that the method worked in a second group of 382 people with and without cancer. Based on their analyses, the test has a negative predictive value of 99.8%, meaning that only 2 in 1,000 individuals tested may be missed and have lung cancer.

    The group’s computer simulations showed that if the test boosted the rate of lung cancer screening to 50% within five years, it could quadruple the number of lung cancers detected and increase the proportion of cancers detected early — when they are most treatable — by about 10%. That could prevent about 14,000 cancer deaths over five years.

    “The test is inexpensive and could be done at a very large scale,” Velculescu says. “We believe it will make lung cancer screening more accessible and help many more people get screened. This will lead to more cancers being detected and treated early.”

    The test is currently available through DELFI Diagnostics for use as a laboratory-based test under the Clinical Laboratory Improvement Amendments. However, the team plans to seek approval from the U.S. Food and Drug Administration for lung cancer screening. Velculescu colleagues also plan to study whether a similar approach could be used to detect other types of cancer.

    Robert B. Scharpf of Johns Hopkins co-authored the study. Additional co-authors were from the Cleveland Clinic, DELFI Diagnostics, Medicus Economics LLC, Miami Cancer Institute, the Pan American Center for Oncology, Washington University, Centura Health, Vanderbilt Health, Stratevi, Massachusetts General Hospital, the Medical University of South Carolina, the Department of Veterans Affairs, the Perelman School of Medicine at the University of Pennsylvania, New York University Langone Health, Allegheny Health Network and Memorial Sloan Kettering Cancer Center.

    The work was supported in part by DELFI Diagnostics, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant, Stand Up To Cancer-DCS International Translational Cancer Research Dream Team Grant, the Gray Foundation, The Honorable Tina Brozman Foundation, the Commonwealth Foundation, the Cole Foundation and the National Institutes of Health.

    Velculescu and Scharpf are inventors on patent applications submitted by The Johns Hopkins University related to cell-free DNA for cancer detection that have been licensed to DELFI Diagnostics, LabCorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana and ManaT Bio. Velculescu divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022. Velculescu is a founder of DELFI Diagnostics, serves on the board of directors, and owns DELFI Diagnostics stock. Scharpf is a founder and consultant of DELFI Diagnostics and owns DELFI Diagnostics stock. Velculescu, Scharpf and Johns Hopkins receive royalties and fees from the company. The Johns Hopkins University also owns equity in DELFI Diagnostics. Velculescu is an adviser to Viron Therapeutics and Epitope. These relationships are managed by Johns Hopkins in accordance with its conflict-of-interest policies.