MSTPublications – June 2025
Adaptive Recruitment Resource Allocation to Improve Cohort Representativeness in Participatory Biomedical Datasets.
Borza VA, Estornell A, Clayton EW, Ho CJ, Rothman RL, Vorobeychik Y, Malin BA.
AMIA Annu Symp Proc. 2025 May 22;2024:192-201. eCollection 2024.
PMID: 40417546 Free PMC article.
Abstract
Large participatory biomedical studies – studies that recruit individuals to join a dataset – are gaining popularity and investment, especially for analysis by modern AI methods. Because they purposively recruit participants, these studies are uniquely able to address a lack of historical representation, an issue that has affected many biomedical datasets. In this work, we define representativeness as the similarity to a target population distribution of a set of attributes and our goal is to mirror the U.S. population across distributions of age, gender, race, and ethnicity. Many participatory studies recruit at several institutions, so we introduce a computational approach to adaptively allocate recruitment resources among sites to improve representativeness. In simulated recruitment of 10,000-participant cohorts from medical centers in the STAR Clinical Research Network, we show that our approach yields a more representative cohort than existing baselines. Thus, we highlight the value of computational modeling in guiding recruitment efforts.
Microstructural Characterization of Short Association Fibers Related to Long-Range White Matter Tracts in Normative Development.
Cho C, Chamberland M, Rheault F, Moyer D, Landman BA, Schilling KG.
Hum Brain Mapp. 2025 Jun 1;46(8):e70255. doi: 10.1002/hbm.70255.
PMID: 40490429 Free PMC article.
Abstract
Short association fibers (SAFs) in the superficial white matter play a key role in mediating local cortical connections but have not been well-studied as innovations in whole-brain diffusion tractography have only recently been developed to study superficial white matter. Characterizing SAFs and their relationship to long-range white matter tracts is crucial to advance our understanding of neurodevelopment during the period from childhood to young adulthood. This study aims to (1) map SAFs in relation to long-range white matter tracts, (2) characterize typical neurodevelopmental changes across these white matter pathways, and (3) investigate the relationship between microstructural changes in SAFs and long-range white matter tracts. Leveraging a cohort of 616 participants ranging in age from 5.6 to 21.9 years old, we performed quantitative diffusion tractography and advanced diffusion modeling with diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). Robust linear regression models were applied to analyze microstructural features, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI). Our results reveal that both SAFs and long-range tracts exhibit similar overall developmental patterns, characterized by negative associations of MD, AD, and RD with age and positive associations of FA, ICVF, ISOVF, and ODI with age. Notably, FA, AD, and ODI exhibit significant differences between SAFs and long-range tracts, suggesting distinct neurodevelopmental trajectories between superficial and deep white matter. In addition, significant differences were found in MD, RD, and ICVF between males and females, highlighting variations in neurodevelopment. This normative study provides insights into typical microstructural changes of SAFs and long-range white matter tracts during development, laying a foundation for future research to investigate atypical development and dysfunction in disease pathology.
Keywords: diffusion MRI; microstructure; neuro‐development; superficial white matter; tractography.
Clinical Characteristics associated with functional seizures in individuals with psychosis.
Lake AM, Reddy IA, Havranek R, Davis LK, Fox J.
Schizophr Res. 2025 May 19;281:209-215. doi: 10.1016/j.schres.2025.05.011. Online ahead of print.
PMID: 40398098 Free article.
Abstract
Background and hypothesis: Functional seizures (FS) are episodes characterized by seizure-like events that are not caused by hypersynchronous neuronal activity. Prior studies have suggested an increased prevalence of psychotic disorders among patients with FS, but results have been inconsistent. We hypothesize that FS are associated with psychosis and that among patients with psychosis, the presence of FS may influence patient clinical characteristics, mortality, and medical resource utilization.
Study design: The association between FS and psychosis was assessed using electronic health records data from a total of 761,848 individuals receiving care at Vanderbilt University Medical Center between 1989 and 2023. Analyses of the association between FS and psychiatric outcomes, sexual trauma, healthcare utilization, and other clinical comorbidities were conducted in a subset of 5219 patients with psychosis.
Study results: Odds of FS were elevated among patients with psychosis compared to controls (OR = 10.09, 95 % CI = 8.40-12.13). Among patients with psychosis, those with FS exhibited higher rates of suicidality (OR = 2.18 95 % CI = 1.50-3.17), catatonia (OR = 2.15, 95 % CI = 1.33-3.45), sexual trauma history (OR = 2.93, 95 % CI = 2.00-4.29) and had a greater number of antipsychotic trials (4.63 versus 3.37, beta = 1.23, SE = 0.18, adjusted p < 0.001) than those without FS. Furthermore, patients with comorbid FS had more hospital presentations at one, three, five, and ten years after receiving a psychosis diagnosis (adjusted p < 0.001).
Conclusions: FS are more common among patients with psychosis and are associated with increased healthcare utilization as well as an increased prevalence of suicidality, catatonia, and certain psychiatric and medical comorbidities.
Keywords: Comorbidities; Functional seizures; Healthcare utilization; Psychosis.
Longitudinal Masked Representation Learning for Pulmonary Nodule Diagnosis from Language Embedded EHRs.
Li TZ, Still JM, Zuo L, Liu Y, Krishnan AR, Sandler KL, Maldonado F, Lasko TA, Landman BA.
medRxiv [Preprint]. 2025 May 11:2025.05.09.25327341. doi: 10.1101/2025.05.09.25327341.
PMID: 40385386 Free PMC article. Preprint.
Abstract
Electronic health records (EHRs) are a rich source of clinical data, yet exploiting longitudinal signals for pulmonary nodule diagnosis remains challenging due to the administrative noise and high level of clinical abstraction present in these records. Because of this complexity, classification models are prone to overfitting when labeled data is scarce. This study explores masked representation learning (MRL) as a strategy to improve pulmonary nodule diagnosis by modeling longitudinal EHRs across multiple modalities: clinical conditions, procedures, and medications. We leverage a web-scale text embedding model to encode EHR event streams into semantically embedded sequences. We then pretrain a bidirectional transformer using MRL conditioned on time encodings on a large cohort of general pulmonary conditions from our home institution. Evaluation on a cohort of diagnosed pulmonary nodules demonstrates significant improvement in diagnosis accuracy with a model finetuned from MRL (0.781 AUC, 95% CI: [0.780, 0.782]) compared to a supervised model with the same architecture (0.768 AUC, 95% CI: [0.766, 0.770]) when integrating all three modalities. These findings suggest that language-embedded MRL can facilitate downstream clinical classification, offering potential advancements in the comprehensive analysis of longitudinal EHR modalities.
Collapse of interictal suppressive networks permits seizure spread.
Makhoul GS, Doss DJ, Johnson GW, Withers CP, Cavender AC, Hidalgo Monroy Lerma B, Reda A, Bibro CE, Liao E, Kang H, Dawant BM, Reddy SB, Crudele AN, Constantinidis C, Roberson SW, Bick SK, Morgan VL, Englot DJ.
Brain. 2025 Jun 6:awaf215. doi: 10.1093/brain/awaf215. Online ahead of print.
PMID: 40473247
Abstract
How do brain networks limit seizure activity? In the Interictal Suppression Hypothesis, we recently postulated that high inward connectivity to seizure onset zones (SOZs) from non-involved zones (NIZs) is a sign of broader network suppression. If broad networks appear to be responsible for interictal SOZ suppression, what changes during seizure initiation, spread, and termination? For patients with drug-resistant epilepsy, intracranial monitoring offers a view into the electrographic networks which organize around and in response to the SOZ. In this manuscript, we investigate network dynamics in the peri-ictal periods to assess possible mechanisms of seizure suppression and the consequences of this suppression being overwhelmed. Peri-ictal network dynamics were derived from stereo electroencephalography recordings from 75 patients with drug-resistant epilepsy undergoing pre-surgical evaluation at Vanderbilt University Medical Center. We computed directed connectivity from 5-second windows in the periods between, immediately before, during, and after 668 seizures. We aligned connectivity matrices across seizures and patients, then calculated net connectivity changes from the SOZ, propagative zone, and NIZ. Across all seizure types, we observed two phases: a rapid increase in directed communication towards the SOZ followed by a collapse in network connectivity. During this first phase, SOZs could be distinguished from all other regions (One-Way ANOVA, P-value = 8.32×10-19-2.22×10-7). In the second phase and post-ictal period, SOZ inward connectivity decreased yet remained distinct (One-Way ANOVA, P-value = 2.58×10-10-1.66×10-2). NIZs appeared to drive increased SOZ connectivity while intra-NIZ connectivity concordantly decreased. Stratifying by seizure subtype, we found that consciousness-impairing seizures decrease inward connectivity from the NIZ earlier than consciousness-sparing seizures (one-way ANOVA, p<0.01 after false discovery correction). Tracking network reorganization against a surrogate for seizure involvement highlighted a possible antagonism between seizure propagation and the NIZ’s ability to maintain high connectivity to the SOZ. Finally, we found that inclusion of peri-ictal connectivity improved SOZ classification accuracy from previous models to a combined area under the curve of 93%. Overall, NIZs appear to actively increase inhibitory signaling towards the SOZ during seizure onset, possibly to thwart seizure activity. While inhibition appears insufficient to prevent seizure onset, the inability to restrict seizure propagation may contribute to loss of consciousness during larger seizures. Dynamic connectivity patterns uncovered in this work may: i) facilitate accurate delineation of surgical targets in focal epilepsy, ii) reveal why interictal suppression of SOZs may be insufficient to prevent all seizures, and iii) provide insight into mechanisms of loss of consciousness during certain seizures.
Keywords: drug-resistant epilepsy; epilepsy surgery; interictal suppression hypothesis; network dynamics; networks; stereo electroencephalography.
Correlates and Consequences of Clonal Hematopoiesis Expansion Rate: A 16-Year Longitudinal Study of 6976 Women.
Pershad Y, Uddin MM, Xue L, Haessler J, Collins JM, Mack T, Glick E, Glaser V, Zhao K, Jaiswal S, Manson JE, Pandey U, Desai P, Natarajan P, Honigberg MC, Kooperberg C, Whitsel EA, Kitzman J, Bick AG, Reiner AP.
Blood. 2025 Jun 11:blood.2025028417. doi: 10.1182/blood.2025028417. Online ahead of print.
PMID: 40499013
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at >4,000x depth of coverage for CHIP mutations in 6,976 postmenopausal women from the Women’s Health Initiative at two timepoints: the WHI baseline exam and approximately 16 years later at the Long Life Study (LLS) visit. Among 3,685 CH mutations detected at baseline (VAF ≥ 0.5%), 24% were not detected at LLS, 26% were micro-CH at LLS (0.5% ≤ VAF < 2%), and 50% were CHIP (VAF ≥ 2%). We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germline variants in TERT, IL6R, TCL1A, and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the Clonal Hematopoiesis Risk Score’s predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.
Changes in Functional Connectivity in Relapsing-Remitting Multiple Sclerosis Spinal Cord Measured via Region-Based and Data-Driven Analyses
Witt A, Combes AJE, Sengupta A, Zhang X, Stubblefield S, McKnight CD, McGonigle T, McGrath M, Stewart I, Sweeney G, Prock LE, Houston D, Vandekar S, O’Grady K.P., Rogers B, Gore J, Smith SA.
Imaging Neuroscience. 2025 Jun 2. doi: 10.1162/IMAG.a.51.
Abstract
The clinical picture of persons with multiple sclerosis (pwMS), a neuroinflammatory disease characterized by demyelination, does not consistently correlate with pathology noted on clinical magnetic resonance imaging (MRI). Functional MRI (fMRI) is a valuable tool to understand neural network alterations resulting from structural damage, with studies in the brain employing both region-of-interest and data-driven assessment of functional connectivity. However, similar studies in the spinal cord (SC) remain limited given the challenge of imaging a small structure in an area with substantial physiologic noise. We sought to apply resting-state fMRI at 3T in the SC of healthy controls (HC) and persons with relapsing-remitting MS (pwRRMS) to assess differences in functional connectivity and relate functional markers to clinicial measures of disability. Consistent with prior SC studies, we determined strongest functional connectivity between ventral gray matter horns in both HCs and pwMS and diminished mobility associated with reduced functional connectivity. Using independent-component analysis, we observed a possible compensatory mechanism of increased connectivity in earlier compared to later stages of relapsing-remitting MS. Further exploration is warranted, and our findings support the notion of functional alterations in the SC of pwMS.
Keywords: Spinal cord, functional magnetic resonance imaging, magnetic resonance imaging, multiple sclerosis, independent component analysis
Oxidized Cell-Free Hemoglobin Induces Mitochondrial Dysfunction by Activation of the Mitochondrial Permeability Transition Pore in the Pulmonary Microvasculature.
Riedmann KJ, Meegan JE, Afzal A, Cervantes-Cruz Y, Obeidalla S, Bogart AM, Ware LB, Shaver CM, Bastarache JA.
Microcirculation. 2025 May;32(4):e70012. doi: 10.1111/micc.70012.
PMID: 40394906 Free PMC article.
Potentiating cancer immunotherapies with modular albumin-hitchhiking nanobody-STING agonist conjugates.
Kimmel BR, Arora K, Chada NC, Bharti V, Kwiatkowski AJ, Finkelstein JE, Hanna A, Arner EN, Sheehy TL, Pastora LE, Yang J, Pagendarm HM, Stone PT, Hargrove-Wiley E, Taylor BC, Hubert LA, Fingleton BM, Gibson-Corley KN, May JC, McLean JA, Rathmell JC, Richmond A, Rathmell WK, Balko JM, Wilson JT.
Nat Biomed Eng. 2025 Jun 11. doi: 10.1038/s41551-025-01400-0. Online ahead of print.
PMID: 40500332
Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells.
Giudice AM, Roth SL, Matlaga S, Cresswell-Clay E, Mishra P, Schürch PM, Boateng-Antwi KAM, Samanta M, Pascual-Pasto G, Zecchino V, Spear TT, McIntyre B, Chada NC, Wang T, Liu L, Wang R, Wilson JT, Wolpaw AJ, Bosse KR.
Mol Ther. 2025 May 27:S1525-0016(25)00395-8. doi: 10.1016/j.ymthe.2025.05.025. Online ahead of print.
PMID: 40437756
Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.
Steiner KK, Young AC, Patterson AR, Sugiura A, Watson MJ, Preston SEJ, Zhelonkin A, Jennings EQ, Chi C, Heintzman DR, Pahnke AP, Toudji YT, Hatem Z, Madden MZ, Arner EN, Sewell AE, Blount AK, Okparaugo R, Fallman E, Krystofiak ES, Sheldon RD, Gibson-Corley KN, Voss K, Nowinski SM, Jones RG, Mogilenko DA, Rathmell JC.
J Immunol. 2025 May 1;214(5):958-976. doi: 10.1093/jimmun/vkaf034.
PMID: 40204636 Free PMC article.
Intraoperative neural firing correlates with motor and cognitive features in Parkinson’s disease.
Hughes NC, Paulo DL, Zargari M, Doss DJ, Narasimhan S, Shults R, Li R, Dawant BM, Dhima K, Kang H, Hassell TJ, Ball TJ, Englot DJ, Bick SK.
J Neurosurg. 2025 May 23:1-10. doi: 10.3171/2025.1.JNS241414. Online ahead of print.
PMID: 40408878
Beyond Phecodes: leveraging PheMAP to identify patients lacking diagnosis codes in electronic health records.
Yan C, Grabowska ME, Thakkar R, Dickson AL, Embí PJ, Feng Q, Denny JC, Kerchberger VE, Malin BA, Wei WQ.
J Am Med Inform Assoc. 2025 Jun 1;32(6):1007-1014. doi: 10.1093/jamia/ocaf055.
PMID: 40156924
Deep learning on brief interictal intracranial recordings can accurately characterize seizure onset zones.
Sundrani S, Johnson GW, Doss DJ, Makhoul GS, Hidalgo Monroy Lerma B, Reda A, Cavender AC, Liao E, Rogers BP, Williams Roberson S, Bick SK, Morgan VL, Englot DJ.
Epilepsia. 2025 May 27. doi: 10.1111/epi.18478. Online ahead of print.
PMID: 40423629
Reducing Surgery for Pediatric Posttonsillectomy Hemorrhage Using Tranexamic Acid: A Quality Improvement Initiative.
Petrauskas LA, Sethurathnam J, Kunnath AJ, Sharma RK, Ceremsak J, Belcher RH, Phillips JD, Werkhaven JA, Whigham AS, Wilcox LJ, Wootten CT, Virgin FW, Park JS.
Otolaryngol Head Neck Surg. 2025 May 21. doi: 10.1002/ohn.1300. Online ahead of print.
PMID: 40396477
The TRIP12 E3 ligase induces SWI/SNF component BRG1-β-catenin interaction to promote Wnt signaling.
Kassel S, Yuan K, Bunnag N, Neitzel LR, Lu W, Schwarzkopf A, Maines B, Loberg MA, Xu G, Adams A, McCray AD, Cho A, Rockouski M, Orton G, Goldsmith L, Aronno MMA, Spencer ZT, Khan OM, Ye F, Williams C, Lebensohn AM, Rohatgi R, Wang X, Weiss VL, Hong CC, Kettenbach AN, Robbins DJ, Ahmed Y, Lee E.
Nat Commun. 2025 Jun 5;16(1):5248. doi: 10.1038/s41467-025-60535-5.
PMID: 40473626 Free PMC article.
Single-cell profiling demonstrates the combined effect of wheeze phenotype and infant viral infection on airway epithelial development.
Berdnikovs S, Newcomb DC, Haruna NF, McKernan KE, Kuehnle SN, Gebretsadik T, McKennan C, Ma S, Cephus JY, Rosas-Salazar C, Anderson LJ, Gern JE, Hartert T.
Sci Adv. 2025 May 23;11(21):eadr9995. doi: 10.1126/sciadv.adr9995. Epub 2025 May 23.
PMID: 40408478 Free PMC article.
Extracorporeal membrane oxygenation bridge to transplant in the era of the lung composite allocation score.
Petree B, Gannon WD, Petrovic M, Stokes JW, Adjei E, Smith RJ, Demarest CT, Hoetzenecker K, Bacchetta M, Trindade AJ.
JHLT Open. 2025 Apr 24;9:100273. doi: 10.1016/j.jhlto.2025.100273. eCollection 2025 Aug.
PMID: 40475035 Free PMC article.
200 Cases of Cardiac Donation after Circulatory Death Utilizing Normothermic Regional Perfusion: The Four-Year Vanderbilt Experience.
Williams AM, Ahmad A, Bommareddi S, Lima B, Pasrija C, Nguyen D, Petrovic M, Wang CC, Quintana E, Siddiqi HK, Amancherla K, Marshall Brinkley D, Lindenfeld J, Menachem J, Ooi H, Pedrotty D, Tsai S, Punnoose L, Rali AS, Sacks S, Wigger M, Zalawadiya S, DeVries SA, Keck CD, Scholl SR, Lepore AJ, Warhoover M, Schlendorf K, Shah AS, Trahanas JM.
J Heart Lung Transplant. 2025 May 31:S1053-2498(25)01974-6. doi: 10.1016/j.healun.2025.05.007. Online ahead of print.
PMID: 40456427 Free article.
Methodological challenges and opportunities when studying the course of autism.
Hus Bal V, Szatmari P, Georgiades S, Gentles SJ, Girault J, Howlin P, Lai MC, Carter Leno V, Lord C, Madgett K, Sheinkopf SJ, Simonoff E, Williams ZJ, Zwaigenbaum L, Halladay A.
Autism. 2025 May 22:13623613251341012. doi: 10.1177/13623613251341012. Online ahead of print.
PMID: 40401338
A cascading effects model of early sensory development in autism.
Russo N, Cascio CJ, Baranek GT, Woynaroski TG, Williams ZJ, Green SA, Schaaf R; Autism Sensory Research Consortium.
Psychol Rev. 2025 Jun 5. doi: 10.1037/rev0000558. Online ahead of print.
PMID: 40471805