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1. Brain aging patterns in a large and diverse cohort of 49,482 individuals.

Author

Yang, Zhijian, Wen, Junhao, Erus, Guray, Govindarajan, Sindhuja, Melhem, Randa, Mamourian, Elizabeth, Cui, Yuhan, Srinivasan, Dhivya, Abdulkadir, Ahmed, Parmpi, Paraskevi, Wittfeld, Katharina, Grabe, Hans, Bülow, Robin, Frenzel, Stefan, Tosun, Duygu, Bilgel, Murat, An, Yang, Yi, Dahyun, Marcus, Daniel, LaMontagne, Pamela, Benzinger, Tammie, Heckbert, Susan, Austin, Thomas, Waldstein, Shari, Evans, Michele, Zonderman, Alan, Launer, Lenore, Sotiras, Aristeidis, Espeland, Mark, Masters, Colin, Maruff, Paul, Fripp, Jurgen, Toga, Arthur, OBryant, Sid, Chakravarty, Mallar, Villeneuve, Sylvia, Johnson, Sterling, Morris, John, Albert, Marilyn, Yaffe, Kristine, Völzke, Henry, Ferrucci, Luigi, Nick Bryan, R, Shinohara, Russell, Fan, Yong, Habes, Mohamad, Lalousis, Paris, Koutsouleris, Nikolaos, Wolk, David, Resnick, Susan, Shou, Haochang, Nasrallah, Ilya, and Davatzikos, Christos

Subjects
Humans, Brain, Aging, Magnetic Resonance Imaging, Male, Female, Aged, Cohort Studies, Middle Aged, Atrophy, Life Style, Adult, Aged, 80 and over
Abstract

Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis.

Published
2024

2. The impact of common and rare genetic variants on bradyarrhythmia development

Author

Weng, Lu-Chen, Rämö, Joel T., Jurgens, Sean J., Khurshid, Shaan, Chaffin, Mark, Hall, Amelia Weber, Morrill, Valerie N., Wang, Xin, Nauffal, Victor, Sun, Yan V., Beer, Dominik, Lee, Simon, Nadkarni, Girish N., Duong, ThuyVy, Wang, Biqi, Czuba, Tomasz, Austin, Thomas R., Yoneda, Zachary T., Friedman, Daniel J., Clayton, Anne, Hyman, Matthew C., Judy, Renae L., Skanes, Allan C., Orland, Kate M., Treu, Timothy M., Oetjens, Matthew T., Alonso, Alvaro, Soliman, Elsayed Z., Lin, Honghuang, Lunetta, Kathryn L., van der Pals, Jesper, Issa, Tariq Z., Nafissi, Navid A., May, Heidi T., Leong-Sit, Peter, Roselli, Carolina, Choi, Seung Hoan, Khan, Habib R., Knight, Stacey, Karlsson Linnér, Richard, Bezzina, Connie R., Ripatti, Samuli, Heckbert, Susan R., Gaziano, J. Michael, Loos, Ruth J. F., Psaty, Bruce M., Smith, J. Gustav, Benjamin, Emelia J., Arking, Dan E., Rader, Daniel J., Shah, Svati H., Roden, Dan M., Damrauer, Scott M., Eckhardt, Lee L., Roberts, Jason D., Cutler, Michael J., Shoemaker, M. Benjamin, Haggerty, Christopher M., Cho, Kelly, Palotie, Aarno, Wilson, Peter W. F., Ellinor, Patrick T., and Lubitz, Steven A.

Published
2025
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4. Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer’s disease continuum

Author

Wen, Junhao, Yang, Zhijian, Nasrallah, Ilya M., Cui, Yuhan, Erus, Guray, Srinivasan, Dhivya, Abdulkadir, Ahmed, Mamourian, Elizabeth, Hwang, Gyujoon, Singh, Ashish, Bergman, Mark, Bao, Jingxuan, Varol, Erdem, Zhou, Zhen, Boquet-Pujadas, Aleix, Chen, Jiong, Toga, Arthur W., Saykin, Andrew J., Hohman, Timothy J., Thompson, Paul M., Villeneuve, Sylvia, Gollub, Randy, Sotiras, Aristeidis, Wittfeld, Katharina, Grabe, Hans J., Tosun, Duygu, Bilgel, Murat, An, Yang, Marcus, Daniel S., LaMontagne, Pamela, Benzinger, Tammie L., Heckbert, Susan R., Austin, Thomas R., Launer, Lenore J., Espeland, Mark, Masters, Colin L., Maruff, Paul, Fripp, Jurgen, Johnson, Sterling C., Morris, John C., Albert, Marilyn S., Bryan, R. Nick, Resnick, Susan M., Ferrucci, Luigi, Fan, Yong, Habes, Mohamad, Wolk, David, Shen, Li, Shou, Haochang, and Davatzikos, Christos

Published
2024
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5. A plasma protein-based risk score to predict hip fractures

Author

Austin, Thomas R., Nethander, Maria, Fink, Howard A., Törnqvist, Anna E., Jalal, Diana I., Buzkova, Petra, Barzilay, Joshua I., Carbone, Laura, Gabrielsen, Maiken E., Grahnemo, Louise, Lu, Tianyuan, Hveem, Kristian, Jonasson, Christian, Kizer, Jorge R., Langhammer, Arnulf, Mukamal, Kenneth J., Gerszten, Robert E., Psaty, Bruce M., Robbins, John A., Sun, Yan V., Skogholt, Anne Heidi, Kanis, John A., Johansson, Helena, Åsvold, Bjørn Olav, Valderrabano, Rodrigo J., Zheng, Jie, Richards, J. Brent, Coward, Eivind, and Ohlsson, Claes

Published
2024
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6. Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function

Author

Zhang, Yuankai, Liu, Xue, Wiggins, Kerri L, Kurniansyah, Nuzulul, Guo, Xiuqing, Rodrigue, Amanda L, Zhao, Wei, Yanek, Lisa R, Ratliff, Scott M, Pitsillides, Achilleas, Aguirre Patiño, Juan Sebastian, Sofer, Tamar, Arking, Dan E, Austin, Thomas R, Beiser, Alexa S, Blangero, John, Boerwinkle, Eric, Bressler, Jan, Curran, Joanne E, Hou, Lifang, Hughes, Timothy M, Kardia, Sharon LR, Launer, Lenore J, Levy, Daniel, Mosley, Thomas H, Nasrallah, Ilya M, Rich, Stephen S, Rotter, Jerome I, Seshadri, Sudha, Tarraf, Wassim, González, Kevin A, Ramachandran, Vasan, Yaffe, Kristine, Nyquist, Paul A, Psaty, Bruce M, DeCarli, Charles S, Smith, Jennifer A, Glahn, David C, González, Hector M, Bis, Joshua C, Fornage, Myriam, Heckbert, Susan R, Fitzpatrick, Annette L, Liu, Chunyu, Satizabal, Claudia L, Aguilera, Norma, Ament, Seth, Ammous, Farah, Arnett, Donna K, Becker, Diane, Bis, Joshua, Blue, Elizabeth, Breaux, Camille, Chaar, Dima, MHI, Clarkson-Townsend, Danielle, Cooper, Brigidann, Coresh, Josef, Correa, Adolfo, DeStefano, Anita, Ding, Jingzhong, Fardo, David, Fitzpatrick, Annette, French, Jennifer, Glahn, David, Gonzalez, Hector, Granot-Hershkovitz, Einat, Hanly, Patrick, Hayden, Kathleen, Heckbert, Susan, Heemann, Scott, Horvath, Steve, Hoth, Karin, Hughes, Timothy, Jaiswal, Sidd, Jian, Xueqiu, Katsumata, Yuriko, Kho, Minjung, Kooperberg, Charles, Launer, Lenore, Lin, Honghuang, Litkowski, Elizabeth, Longstreth, Will, Martin, Alexandra, Mayeux, Richard, Mikulla, Julie, Miller, Amy, Misra, Biswapriya, Mosley, Thomas, Nyquist, Paul, O'Connell, Jeff, Olivier, Michael, Peloso, Gina, Perry, James, Psaty, Bruce, Purcell, Shaun, and Raffield, Laura

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Acquired Cognitive Impairment, Neurodegenerative, Precision Medicine, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biomedical Imaging, Alzheimer's Disease, Clinical Research, Dementia, Behavioral and Social Science, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Neurological, Mental health, Good Health and Well Being, Middle Aged, Humans, Female, Aged, Male, DNA, Mitochondrial, DNA Copy Number Variations, Prospective Studies, Cross-Sectional Studies, Alzheimer Disease, Magnetic Resonance Imaging, Cognition, Brain, NHLBI Trans-Omics for Precision Medicine (TOPMed) program, Mitochondrial and Neurocognitive Working Groups, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and objectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (

Published
2023

9. Publisher Correction: A plasma protein-based risk score to predict hip fractures

Author

Austin, Thomas R., Nethander, Maria, Fink, Howard A., Törnqvist, Anna E., Jalal, Diana I., Buzkova, Petra, Barzilay, Joshua I., Carbone, Laura, Gabrielsen, Maiken E., Grahnemo, Louise, Lu, Tianyuan, Hveem, Kristian, Jonasson, Christian, Kizer, Jorge R., Langhammer, Arnulf, Mukamal, Kenneth J., Gerszten, Robert E., Psaty, Bruce M., Robbins, John A., Sun, Yan V., Skogholt, Anne Heidi, Kanis, John A., Johansson, Helena, Åsvold, Bjørn Olav, Valderrabano, Rodrigo J., Zheng, Jie, Richards, J. Brent, Coward, Eivind, and Ohlsson, Claes

Published
2024
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10. Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging

Author

Short, Meghan I, Fohner, Alison E, Skjellegrind, Håvard K, Beiser, Alexa, Gonzales, Mitzi M, Satizabal, Claudia L, Austin, Thomas R, Longstreth, WT, Bis, Joshua C, Lopez, Oscar, Hveem, Kristian, Selbæk, Geir, Larson, Martin G, Yang, Qiong, Aparicio, Hugo J, McGrath, Emer R, Gerszten, Robert E, DeCarli, Charles S, Psaty, Bruce M, Vasan, Ramachandran S, Zare, Habil, and Seshadri, Sudha

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Prevention, Brain Disorders, Aging, Neurodegenerative, Acquired Cognitive Impairment, Dementia, Clinical Research, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, Humans, Proteome, Proteomics, Brain, Alzheimer Disease, Biomarkers, Magnetic Resonance Imaging, Inflammation, Alzheimer's disease, biomarkers, dementia, endophenotypes, magnetic resonance imaging, proteomics, Alzheimer’s disease, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundAlzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults.ObjectiveTo identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome.MethodsWeighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up).ResultsTwo proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities.ConclusionsProteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

Published
2023

11. Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Author

Tin, Adrienne, Fohner, Alison E, Yang, Qiong, Brody, Jennifer A, Davies, Gail, Yao, Jie, Liu, Dan, Caro, Ilana, Lindbohm, Joni V, Duggan, Michael R, Meirelles, Osorio, Harris, Sarah E, Gudmundsdottir, Valborg, Taylor, Adele M, Henry, Albert, Beiser, Alexa S, Shojaie, Ali, Coors, Annabell, Fitzpatrick, Annette L, Langenberg, Claudia, Satizabal, Claudia L, Sitlani, Colleen M, Wheeler, Eleanor, Tucker-Drob, Elliot M, Bressler, Jan, Coresh, Josef, Bis, Joshua C, Candia, Julián, Jennings, Lori L, Pietzner, Maik, Lathrop, Mark, Lopez, Oscar L, Redmond, Paul, Gerszten, Robert E, Rich, Stephen S, Heckbert, Susan R, Austin, Thomas R, Hughes, Timothy M, Tanaka, Toshiko, Emilsson, Valur, Vasan, Ramachandran S, Guo, Xiuqing, Zhu, Yineng, Tzourio, Christophe, Rotter, Jerome I, Walker, Keenan A, Ferrucci, Luigi, Kivimäki, Mika, Breteler, Monique MB, Cox, Simon R, Debette, Stephanie, Mosley, Thomas H, Gudnason, Vilmundur G, Launer, Lenore J, Psaty, Bruce M, Seshadri, Sudha, and Fornage, Myriam

Subjects
Biochemistry and Cell Biology, Biological Sciences, Prevention, Acquired Cognitive Impairment, Brain Disorders, Neurosciences, Aging, Alzheimer's Disease, Behavioral and Social Science, Dementia, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, Middle Aged, Humans, Aged, Alzheimer Disease, Cognition, Cognitive Dysfunction, Neurons, Biomarkers, Biological sciences, Biomedical and clinical sciences
Abstract

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Published
2023

12. A Comparison of Static, Dynamic, and Hybrid Analysis for Malware Detection

Author

Damodaran, Anusha, Di Troia, Fabio, Corrado, Visaggio Aaron, Austin, Thomas H., and Stamp, Mark

Subjects
Computer Science - Cryptography and Security, Computer Science - Machine Learning
Abstract

In this research, we compare malware detection techniques based on static, dynamic, and hybrid analysis. Specifically, we train Hidden Markov Models (HMMs ) on both static and dynamic feature sets and compare the resulting detection rates over a substantial number of malware families. We also consider hybrid cases, where dynamic analysis is used in the training phase, with static techniques used in the detection phase, and vice versa. In our experiments, a fully dynamic approach generally yields the best detection rates. We discuss the implications of this research for malware detection based on hybrid techniques.

Published
2022
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18. Life's Simple 7 Cardiovascular Health Score in Relation to Arrhythmias on Extended Ambulatory Electrocardiographic Monitoring (from the Multi-Ethnic Study of Atherosclerosis)

Author

Ma, Yuyang, Floyd, James S, Austin, Thomas R, Chen, Lin Yee, Horwich, Tamara, Post, Wendy S, Michos, Erin D, and Heckbert, Susan R

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Atherosclerosis, Heart Disease, Cardiovascular, Aging, Good Health and Well Being, Aged, Atrial Fibrillation, Cardiovascular Diseases, Electrocardiography, Ambulatory, Exercise, Humans, Longitudinal Studies, Male, Risk Factors, United States, Ventricular Premature Complexes, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

The Life's Simple 7 (LS7) metric consists of 7 modifiable health behaviors and measures that are known health factors for cardiovascular wellness. Relatively little is known about the association of LS7 score with cardiac arrhythmias. In the setting of the Multi-Ethnic Study of Atherosclerosis, we studied the LS7 score (range 0 to 14), assessed at the 2010 to 2102 study visit, in relation to cardiac arrhythmias assessed by Zio Patch ambulatory electrocardiographic monitoring in 2016 to 2018. In participants free of clinically recognized cardiovascular disease and atrial fibrillation, we used logistic and linear regression to examine the association of total LS7 score with atrial fibrillation, supraventricular ectopy, and ventricular ectopy. In 1,329 participants in the analysis, the mean (SD) age was 67 (8) years and 48% were men. A more favorable total LS7 score was associated with fewer premature ventricular contractions (PVCs) per hour (ratio of geometric means for optimal [11 to 14] versus inadequate [0 to 7] score 0.52 [95% confidence interval 0.34 to 0.81]). After adjustment for sociodemographic characteristics, the association was attenuated (0.66 [0.43 to 1.01]). =Among the LS7 components, a more favorable body mass index was associated with less ventricular ectopy. We did not detect associations of total LS7 score with atrial arrhythmias. In conclusion, in this longitudinal study of older participants free of clinically recognized cardiovascular disease, there was little evidence of association of the LS7 cardiovascular health score with subclinical cardiac arrhythmias. However, there was a suggestion that a more favorable LS7 score was associated with fewer PVCs and specifically, that a more favorable body mass index was associated with fewer PVCs.

Published
2022

29. A Blockchain-Based Tamper-Resistant Logging Framework

Author

Austin, Thomas H., Di Troia, Fabio, Filipe, Joaquim, Editorial Board Member, Ghosh, Ashish, Editorial Board Member, Prates, Raquel Oliveira, Editorial Board Member, Zhou, Lizhu, Editorial Board Member, Bathen, Luis, editor, Saldamli, Gokay, editor, Sun, Xiaoyan, editor, Austin, Thomas H., editor, and Nelson, Alex J., editor

Published
2022
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30. Crowdfunding Non-fungible Tokens on the Blockchain

Author

Basu, Sean, Basu, Kimaya, Austin, Thomas H., Filipe, Joaquim, Editorial Board Member, Ghosh, Ashish, Editorial Board Member, Prates, Raquel Oliveira, Editorial Board Member, Zhou, Lizhu, Editorial Board Member, Chang, Sang-Yoon, editor, Bathen, Luis, editor, Di Troia, Fabio, editor, Austin, Thomas H., editor, and Nelson, Alex J., editor

Published
2022
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31. Management of infliximab refractory immune checkpoint inhibitor gastrointestinal toxicity: a multicenter case series

Author

Lisa Zimmer, Bastian Schilling, Yinghong Wang, Georgina V Long, Jennifer McQuade, Ana Arance, Douglas B Johnson, Nadia Yousaf, Kazi J Nahar, Matteo S Carlino, Kate Young, Joanna Lee, Liselotte Tas, Serigne N Lo, Christian Blank, Alexander Maxwell Menzies, Catriona Harvey, Janet McKeown, Sheima Farag, Aafke Meerveld-Eggink, Austin Thomas, and Roberto Martín Huertas

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.Methods We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.Results 78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox and progressive disease).Conclusions IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.

Published
2024
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34. Malware Detection Using Dynamic Birthmarks

Author

Vemparala, Swapna, Di Troia, Fabio, Visaggio, Corrado A., Austin, Thomas H., and Stamp, Mark

Subjects
Computer Science - Cryptography and Security, Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

In this paper, we explore the effectiveness of dynamic analysis techniques for identifying malware, using Hidden Markov Models (HMMs) and Profile Hidden Markov Models (PHMMs), both trained on sequences of API calls. We contrast our results to static analysis using HMMs trained on sequences of opcodes, and show that dynamic analysis achieves significantly stronger results in many cases. Furthermore, in contrasting our two dynamic analysis techniques, we find that using PHMMs consistently outperforms our analysis based on HMMs., Comment: Extended version of conference paper

Published
2019

35. De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population

Author

Kessler, Michael D, Loesch, Douglas P, Perry, James A, Heard-Costa, Nancy L, Taliun, Daniel, Cade, Brian E, Wang, Heming, Daya, Michelle, Ziniti, John, Datta, Soma, Celedón, Juan C, Soto-Quiros, Manuel E, Avila, Lydiana, Weiss, Scott T, Barnes, Kathleen, Redline, Susan S, Vasan, Ramachandran S, Johnson, Andrew D, Mathias, Rasika A, Hernandez, Ryan, Wilson, James G, Nickerson, Deborah A, Abecasis, Goncalo, Browning, Sharon R, Zöllner, Sebastian, O’Connell, Jeffrey R, Mitchell, Braxton D, Lung, and Blood Institute Trans-Omics for Precision Medicine Consortium National Heart, Group, TOPMed Population Genetics Working, O’Connor, Timothy D, Aalbers, Sanne, Abdalla, Moustafa, Abdul-Rahman, Omar, Abecasis, Gonçalo, Abhyankar, Avinash, Adrianto, Indra, Aguet, Francois, Akers, Rachel, Al-Tobasei, Rafet, Albert, Christine, Aldred, Micheala, Almasy, Laura, Almeida, Marcio, Alonso, Alvaro, Ament, Seth, Ampleford, Elizabeth, An, Ping, Anderson, Christopher D, Andersson, Charlotte, Anugu, Pramod, Appelbaum, Elizabeth, Ardlie, Kristin, Arking, Dan, Armasu, Sebastian M, Arnett, Donna K, Arruda, Heather, Arvanitis, Marios, Ashley-Koch, Allison, Ashrani, Aneel, Aslibekyan, Stella, Assimes, Tim, Atkinson, Elizabeth, Auer, Paul, Austin, Thomas R, Avery, Christy, Avila-Pacheco, Julian, Avillach, Paul, Aviv, Abraham, Avramopoulos, Dimitrios, Ballantyne, Christie, Balte, Pallavi, Bamshad, Michael, Bancks, Mike, Barnard, John, Barr, R Graham, Barron-Casella, Emily, Bartz, Traci, Barwick, Lucas, Basu, Saonli, Battle, Alexis, Baumann, Michael, Beame, David, Beaty, Terri, Beck, Gerald, Becker, Lewis, Becker, Diane, Beer, Rebecca, Begum, Ferdouse, Beiser, Alexa, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Berk-Rauch, Hanna, Besich, Zachary M, Bezerra, Marcos, Bhatt, Surya, Bi, Wenjian, Bick, Alexander, and Bielak, Larry

Subjects
Biological Sciences, Genetics, Biotechnology, Human Genome, Precision Medicine, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Amish, Cohort Studies, DNA Mutational Analysis, Female, Genetics, Population, Genome, Human, Heterozygote, Humans, Male, Mutation, Pedigree, Whole Genome Sequencing, Young Adult, National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Population Genetics Working Group, de novo mutations, diversity, mutation rate, recombination
Abstract

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains

Published
2020

39. Abstract 13259: Large-Scale Plasma Proteomics Identifies C1QTNF1 as a Potential Causal Risk Factor for Aortic Stenosis

Author

Shelbaya, Khaled A, Lamberson, Victoria, Yang, Yimin, Dorbala, Pranav, Buckley, Leo, Claggett, Brian, Skali, Hicham, Dufresne, Line, Engert, Jamie C, Yang, Ta-Yu, Thanassoulis, George, Floyd, James S, Austin, Thomas, Bortnick, Anna E, Kizer, Jorge R, Costade Freitas, Renata Caroline C, Singh, Sasha A, Aikawa, Elena, Ballantyne, Christie M, Hoogeveen, Ron C, Yu, Bing, Coresh, Josef, Matsushita, Kuni, and Shah, Amil M

Published
2023
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40. Abstract 13260: Large Scale Plasma Proteomics Identifies MMP-12 as a Novel Biomarker of Aortic Stenosis Progression

Author

Shelbaya, Khaled, Lamberson, Victoria, Yang, Yimin, Dorbala, Pranav, Buckley, Leo, Claggett, Brian, Skali, Hicham, Dufresne, Line, Thanassoulis, George, Yang, Ta-Yu, Engert, Jamie C, Floyd, James S, Austin, Thomas, Bortnick, Anna E, Kizer, Jorge R, Costade Freitas, Renata Caroline C, Singh, Sasha A, Aikawa, Elena, Ballantyne, Christie M, Hoogeveen, Ron C, Yu, Bing, Coresh, Josef, Matsushita, Kuni, and Shah, Amil M

Published
2023
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41. Genome-wide analyses identify SCN5A as a susceptibility locus for premature atrial contraction frequency

Author

Thériault, Sébastien, Imboden, Medea, Biggs, Mary L., Austin, Thomas R., Aeschbacher, Stefanie, Schaffner, Emmanuel, Brody, Jennifer A., Bartz, Traci M., Risch, Martin, Grossmann, Kirsten, Lin, Henry J., Soliman, Elsayed Z., Post, Wendy S., Risch, Lorenz, Krieger, Jose E., Pereira, Alexandre C., Heckbert, Susan R., Sotoodehnia, Nona, Probst-Hensch, Nicole M., and Conen, David

Published
2022
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42. Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing

Author

Austin, Thomas R., McHugh, Caitlin P., Brody, Jennifer A., Bis, Joshua C., Sitlani, Colleen M., Bartz, Traci M., Biggs, Mary L., Bansal, Nisha, Buzkova, Petra, Carr, Steven A., deFilippi, Christopher R., Elkind, Mitchell S. V., Fink, Howard A., Floyd, James S., Fohner, Alison E., Gerszten, Robert E., Heckbert, Susan R., Katz, Daniel H., Kizer, Jorge R., Lemaitre, Rozenn N., Longstreth, W. T., McKnight, Barbara, Mei, Hao, Mukamal, Kenneth J., Newman, Anne B., Ngo, Debby, Odden, Michelle C., Vasan, Ramachandran S., Shojaie, Ali, Simon, Noah, Smith, George Davey, Davies, Neil M., Siscovick, David S., Sotoodehnia, Nona, Tracy, Russell P., Wiggins, Kerri L., Zheng, Jie, and Psaty, Bruce M.

Published
2022
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47. Adaptive Squeeze-and-Shrink Image Denoising for Improving Deep Detection of Cerebral Microbleeds

Author

Liu, Hangfan, Rashid, Tanweer, Ware, Jeffrey, Jensen, Paul, Austin, Thomas, Nasrallah, Ilya, Bryan, Robert, Heckbert, Susan, Habes, Mohamad, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, Yung, Moti, Editorial Board Member, de Bruijne, Marleen, editor, Cattin, Philippe C., editor, Cotin, Stéphane, editor, Padoy, Nicolas, editor, Speidel, Stefanie, editor, Zheng, Yefeng, editor, and Essert, Caroline, editor

Published
2021
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49. Pembrolizumab-associated acral necrosis and esophageal necrosis

Author

Austin Thomas, Athira Jayan, Yusuf Chang, Reese Svetgoff, Saumil Datar, Vinayak Memula, Michael Huang, Laura Winikka, and Jeffrey Chen

Subjects
Immune checkpoint inhibitor, Acral necrosis, Esophageal necrosis, Immunotoxicity, Immunotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various advanced malignancies. By unleashing the immune system from its natural self-autoregulating mechanisms, malignant cells throughout the body are more effectively destroyed. These new immunotherapies have been used for a variety of cancers including cancer of the lung, colon, skin, prostate, and more. Although these therapies provide an effective mechanism at treating cancer, they unfortunately come with undesirable autoimmune side effects known as immune-related adverse events (irAEs). Here, we present a unique case of a patient who developed rare irAEs following ICI treatment. The patient was a 60-year-old male with stage IV lung adenocarcinoma who was treated with one dose of maintenance pembrolizumab after gamma radiation and chemotherapy. He subsequently developed acral necrosis requiring digital amputations followed by esophageal necrosis requiring gastrostomy tube placement. Out of concern for ICI-related acral necrosis, he was treated with prednisone, tocilizumab, pentoxifylline, amlodipine, and aspirin. He was readmitted one month later for worsened digital ischemia and received another round of pentoxifylline but unfortunately required digital amputations in the outpatient setting. He was admitted again about one month later for severe ulcerative necrosis of the entire esophagus and restarted on a high-dose prednisone taper for suspected ICI-induced esophageal necrosis. At the latest follow-up, the patient was successfully tapered off steroids and had no recurrent digital ischemia or esophagitis symptoms. As this case highlights, it is critical that providers recognize early symptoms of digital ischemia in patients receiving immunotherapy, and that these patients may be at risk for ischemic events in other body systems, such as the gastrointestinal system. Early cessation of ICIs, aggressive immunosuppression, and supportive measures could potentially lead to both preservation of the digits and GI tract. Further studies of optimal treatment strategies for these rare irAEs are warranted.

Published
2022
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