medRxiv : the preprint server for health sciences最新文献

{"title":"Orthogonal validation of PD Biomarkers: Multi-platform proteomics profiling of CSF, Plasma, and Urine confirms DDC as a consistent candidate.","authors":"Ravindra Kumar, Aleksandra Beric, Daniel Western, Zining Yang, Wenjing Lin, Jigyasha Timsina, Carlos Cruchaga, Laura Ibanez","doi":"10.1101/2025.09.25.25336658","DOIUrl":"https://doi.org/10.1101/2025.09.25.25336658","url":null,"abstract":"<p><strong>Background: </strong>High throughput proteomics has enabled hypothesis free biomarker discovery. However, differences in sample sizes, biological fluid, and quantification technologies have limited replication and validation of the results, and studies on the cross-platform variability are lacking. Here, we present the first orthogonal validation across three platforms in Parkinson's disease (PD) to understand the technical and biological challenges of proteomic studies.</p><p><strong>Methods: </strong>We have leveraged publicly available proteomic data from cerebrospinal fluid (CSF), plasma, and urine within the Parkinson's Progression Markers Initiative (PPMI) cohort, generated using SomaScan5K (CSF), mass spectrometry (MS; CSF, plasma, and urine), and Olink Explore (CSF and plasma). Across platforms, we compared 375 proteins that were consistently quantified. We performed differential abundance analysis comparing PD versus healthy controls followed by sensitivity analyses (mutation carriers, at-risk participants, longitudinal analyses) to further understand the findings.</p><p><strong>Results: </strong>In CSF, we found significant correlations between effect sizes from the 375 proteins quantified by SomaScan5K and MS (ρ=0.42, p=2.60×10 □ □), as well as SomaScan5K and Olink Explore (ρ=0.15, p=3.15×10□ ³ ) while MS and Olink Explore showed no significant correlations in CSF or plasma. Orthogonal validation identified two proteins (DLK1, GSTA3) replicated between SomaScan5K and Olink Explore and seven proteins (ALCAM, CHL1, CNDP1, NCAM2, PEBP1, PTPRS, SCG2) replicated between MS and SomaScan5K. No proteins replicated between MS and Olink Explore in CSF or plasma. DDC showed consistent dysregulation across analyses. In CSF (Olink Explore), it was dysregulated in PD participants (beta=0.79, p=8.49×10 ^-16 ), and in at-risk individuals (beta=0.64, p=1.41×10 ^-7 ) including those with hyposmia (beta=0.70, p=2.13×10 ^-5 ) and REM Sleep Behavior Disorder (beta=0.52, p=1.00×10 ^-3 ). In urine, DDC was higher in at-risk individuals (beta=0.43, p=7.28×10 ^-5 ), driven by <i>LRRK2</i> ⁺ at-risk participants (beta=0.59, p=1.74×10 ^-6 ), as well as in symptomatic mutation carriers, <i>LRRK2</i> ⁺ (beta=0.68, p=9.08×10 ^-8 ), and <i>GBA</i> ^<i>+</i> (beta=0.28, p=0.04).</p><p><strong>Conclusions: </strong>Biologically, these findings add further evidence that DDC has strong potential as a biomarker. Methodologically, our findings emphasize that platform selection can introduce more variance than that originating from disease status, which limits the reproducibility across technologies. This highlights the challenges and importance of cross-platform validation in proteomic biomarker research, and the translation of those discoveries to the clinic.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Modern Utility of Awake Deep Brain Stimulation Surgery.","authors":"Bryan T Klassen, Matthew R Baker, Kai J Miller","doi":"10.1101/2025.09.25.25336654","DOIUrl":"https://doi.org/10.1101/2025.09.25.25336654","url":null,"abstract":"<p><strong>Background: </strong>Awake deep brain stimulation (DBS) surgery with microelectrode recording (MER) and test stimulation offers real-time physiologic feedback to refine lead placement, but its relevance is increasingly debated in an era of advanced imaging and streamlined asleep workflows.</p><p><strong>Objective: </strong>To describe a contemporary framework for awake DBS with MER and to evaluate whether, in our hands, this approach results in a final lead position different from what we would have achieved with asleep DBS.</p><p><strong>Methods: </strong>We outline a standardized workflow combining high-resolution imaging, confirmatory MER, and intraoperative stimulation mapping for an example context of thalamic targeting for essential tremor. To quantify the impact of the awake approach on surgical decision making, we retrospectively reviewed the first 137 consecutively implanted VIM DBS leads placed (awake) by a single surgeon working with a single intraoperative neurologist. In each case, we recorded whether the final lead was implanted along the planned target, whether it was adjusted in depth along the planned trajectory, or whether it was moved to a parallel track. For the parallel track moves, we compared the final lead position to the initially planned imaging target using co-registered pre- and postoperative imaging.</p><p><strong>Results: </strong>Among 137 consecutive leads implanted, 116 were implanted in the planned trajectory, with 49 at the planned depth and 67 at an adjusted depth. Twenty-one of the 137 leads were placed along a parallel trajectory based on intraoperative findings, with seventeen having available imaging for further analysis. Post-operative analysis showed that only 2 of the 17 were moved toward the intended target. The remaining 15 were moved away (13) or equidistant (2) from the intended target.</p><p><strong>Conclusion: </strong>Feedback from MER and test stimulation in awake DBS cases frequently informs surgical adjustments that deviate from the planned trajectory, often in response to patient-specific physiology not captured by imaging. In the vast majority of our cases, these adjustments would not have been made using an asleep DBS approach, since moves were not made toward the planned target. This indicates that, in our practice, awake surgery results in adjustment of lead position in response to discovered functional anatomy rather than to correct stereotactic inaccuracy. Our findings underscore the continued utility in our practice of awake DBS with MER in tailoring therapy to individual anatomy and functional organization.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ecological Assessment of Transdiagnostic Clinical Symptoms in Serious Mental Illness with Daily Smartphone Surveys.","authors":"Yoonho Chung, Bryce Gillis, Habiballah Rahimi-Eichi, Vincent Holstein, Jeffrey M Girard, Scott L Rauch, Dost Öngür, Einat Liebenthal, Justin T Baker","doi":"10.1101/2025.09.26.25336721","DOIUrl":"https://doi.org/10.1101/2025.09.26.25336721","url":null,"abstract":"<p><p>Clinical symptoms in serious mental illness (SMI) fluctuate dynamically, yet standard interview-based assessments often fail to capture these daily changes. Smartphone-based ecological surveys offer a scalable approach to monitoring symptoms in naturalistic settings. We analyzed longitudinal data from 56 outpatients with psychotic or affective disorders who completed 12,984 daily surveys and 1,028 clinical assessments over one year. Machine learning models showed that smartphone surveys moderately estimated Montgomery-Åsberg Depression Rating Scale (r _rm = 0.57; p < 0.001) and Young Mania Rating Scale (r _rm = 0.39; p < 0.001) and reliably captured within-person fluctuations. Positive symptoms measured by the Positive and Negative Syndrome Scale were also correlated (r _rm = 0.24, p < 0.001), though with variable accuracy across participants. Factor modeling showed strongest convergence in negative affective domains, with symptom severity not affecting adherence. These findings highlight smartphone surveys as an ecologically valid tool for real-time symptom monitoring in SMI.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Racial and Socioeconomic Fairness of Area-Level Traffic-Related Air Pollution Measure Aggregation.","authors":"Andrew Vancil, Stephen Colegate, Erika Rasnick Manning, Anushka Palipana, Rhonda Szczesniak, Cole Brokamp","doi":"10.1101/2025.09.26.25336652","DOIUrl":"https://doi.org/10.1101/2025.09.26.25336652","url":null,"abstract":"<p><strong>Background: </strong>The Environmental Protection Agency's Environmental Justice Screen traffic proximity (EJ Screen) and the Department of Transportation's Average Annual Daily Traffic (AADT) commonly serve as proxies of traffic-related pollution exposure. However, the methods used to aggregate to area-level measures have been untested for bias.</p><p><strong>Methods: </strong>Using a parcel-level measured developed for Hamilton County, Ohio, agreement was determined with both above measures at three geographic levels: census block group, census tract and zip code tabulation area (ZCTA). Fairness was assessed using linear regression.</p><p><strong>Results: </strong>Generally, the values of AADT were in significant agreement with the parcel proximity measure while the EJ Screen was not. Racial and community deprivation bias was widely detected for EJ Screen.</p><p><strong>Discussion: </strong>While the biases detected were not directly against majority black and materially deprived neighborhoods, the biases could manifest in negative downstream effects. These manifestations include suppression of known traffic-related pollution effects in subsequent research.</p><p><strong>Impact statement: </strong>The Environmental Protection Agency's Environmental Justice Screen traffic proximity (EJ Screen) and the Department of Transportation's Average Annual Daily Traffic (AADT) are widely used traffic related pollution proxies however, with common aggregation techniques largely untested for fairness, this research has detected potential biases in the EJ Screen product.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optical Microscopy Predictions of Focal Recurrence in Glioblastoma.","authors":"Sanjeev Herr, Niels Olshausen, Melike Pekmezci, Jasleen Kaur, Youssef Sibih, Vardhaan Ambati, Katie Scotford, Amit Persad, Thiebaud Picart, Akhil Kondepudi, Nancy Ann Oberheim-Bush, Albert Kim, Jacob Young, Mitchel S Berger, Madhumita Sushil, Todd Hollon, Shawn L Hervey-Jumper","doi":"10.1101/2025.09.24.25336541","DOIUrl":"https://doi.org/10.1101/2025.09.24.25336541","url":null,"abstract":"<p><p>A hallmark of glioblastoma (GBM) is disease recurrence, which occurs in all patients despite tumor resection, radiation, and chemotherapy. A critical challenge in glioblastoma treatment is the management of recurrent disease, for which there is no standard of care. Predicting the location of glioblastoma recurrence may improve the efficiency of advanced-stage therapies. Here, we present an artificial intelligence (AI)-based model to predict the risk of unprocessed surgical tissues at initial resection. AI-informed label-free optical microscopy was used to generate a normalized tumor infiltration value (AI-infiltration) for whole-slide optical images of samples taken from resection cavity margins. These values, in combination with clinical, radiographic, and molecular variables, were used to build a predictive model of focal recurrence. In a cohort of 80 patients, comprising 367 samples and 133,454 unique images, glioblastoma infiltration was significantly higher in margin samples from recurrent tumors (p = 0.026) compared with those from non-recurrent tumors. A random forest (RF) machine learning classifier was able to predict site recurrence with an average area under the receiver operating characteristic curve (AUC) of 86.6% ± 10.0 for the training cohort and 80.3% (95% CI: 0.641-0.965) for the validation cohort. AI-infiltration was the strongest contributor to recurrence prediction, outperforming tumor molecular features. Model performance remained high regardless of tumor location, resulting in random forest model predictions of recurrence at 5 and 10 millimeters of each sampled site. These findings represent the potential of AI to predict sites of tumor recurrence, thereby improving accessibility to targeted, precision, multimodal therapy for the highest-risk areas of disease. <b>One Sentence Summary:</b> Machine learning estimates of tumor infiltration predict focal glioblastoma recurrence.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wearable Devices Detect Physiological Changes that Precede and Are Associated with Symptomatic and Inflammatory Rheumatoid Arthritis Flares.","authors":"Pragya Sharma, Matteo Danieletto, Jessica K Whang, Kyle Landell, Drew Helmus, Bruce E Sands, Mayte Suarez-Farinas, Percio S Gulko, Robert P Hirten","doi":"10.1101/2025.09.24.25336585","DOIUrl":"https://doi.org/10.1101/2025.09.24.25336585","url":null,"abstract":"<p><p>Physiological parameters are altered in rheumatoid arthritis (RA). We evaluated whether changes in physiological metrics, collected from wearable devices, identify and precede the development of both symptomatic and inflammatory RA flares. Participants with RA answered daily disease activity surveys and provided laboratory assessments of inflammatory activity. They wore an Apple Watch (n=35), Fitbit (n=17), or Oura Ring (n=3) collecting heart rate (HR), resting heart rate (RHR), heart rate variability (HRV), and steps. Linear mixed effect models were used to associate HR, RHR and steps with flare and remission periods. Cosinor mixed effect models assessed circadian features of HRV. Mixed effect logistic regression models evaluated changes in physiological metrics prior to the onset of flares. The study enrolled 53 participants (88.7% female) with a mean age of 51.1 (SD 15.2) years. Each contributed a mean of 105 (SD 97) days of data. Mean steps were lower, while mean nighttime HR was higher during symptomatic periods, compared to periods of symptomatic remission. Means daily HR, daytime HR, nighttime HR, and RHR were higher during periods of inflammatory flares, compared to inflammatory remission. Circadian features of HRV differentiated inflammatory and symptomatic flares from remission. All metrics were altered up to 4 weeks prior to inflammatory and symptomatic flare development. This suggests the potential use of wearable devices for disease monitoring and flare prediction.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-effectiveness of endovascular versus open surgery for chronic limb-threatening ischemia.","authors":"Zafar Zafari, Mehdi Najafzadeh, Mufaddal Mahesri, HoJin Shin, Philip P Goodney, Michael S Conte, Mark A Creager, Michael D Dake, Michael R Jaff, John A Kaufman, Richard J Powell, Chris J White, Michael B Strong, Kenneth Rosenfield, Alik Farber, Matthew T Menard, Niteesh K Choudhry","doi":"10.1101/2025.09.22.25336403","DOIUrl":"https://doi.org/10.1101/2025.09.22.25336403","url":null,"abstract":"<p><strong>Background: </strong>Revascularization for Chronic Limb-Threatening Ischemia (CLTI) may be performed with an endovascular (Endo) or open surgical (Bypass) approach.</p><p><strong>Objective: </strong>To evaluate the cost-effectiveness of Endo versus Bypass surgery for CLTI using data from the Best Endovascular versus Best Surgical Therapy for Patients with CLTI (BEST-CLI) trial.</p><p><strong>Methods: </strong>We developed an individual-level continuous time Markov model that included health states representing the occurrence of adjudicated clinical events from BEST-CLI. Rates of clinical outcomes and health utilities were derived directly from trial data. Costs came from Medicare insurance claims data and physician fee schedule. We calculated the incremental cost per life years gained, incremental quality-adjusted life years (QALYs) gained, incremental net monetary benefit (INMB) and cost per major events of amputation, revascularization, and myocardial infarction (MI) or stroke avoided over a 5- and 10-year time horizon. Sensitivity analyses were performed using a Monte Carlo simulation.</p><p><strong>Results: </strong>In base case analyses conducted over a 5-year time horizon, the mean per person direct medical costs were $227,341 (95% Credible Interval [CrI]: $173,075, $291,443) for Bypass and $243,614 (95% CrI: $190,112, $305,605) for Endo. The mean survival per person was 3.91 years (95% CrI: 3.78, 4.03) for Bypass and 3.88 years (95% CrI: 3.68, 4.06) for Endo. This resulted in Endo being dominated by Bypass surgery with respect to costs per life year gained. The mean QALYs per person were 2.48 (95% CrI: 1.11, 3.49) for Bypass and 2.54 (95% CrI: 1.39, 3.40) for Endo, resulting in an incremental costs per QALY gained of $263,973/QALY and an INMB of -$10,109 (95% CrI: -$168,908, $157,433) at a $100,000/QALY willingness-to-pay threshold for Endo vs. Bypass. The results over 10 years were consistent with those of the 5-year follow-up. In the Monte Carlo simulation, there was only a 55% chance that Bypass was more cost-effective than Endo.</p><p><strong>Conclusion: </strong>In the base case analysis, Bypass was the preferred strategy with respect to survival and QALYs, at conventional willingness to pay thresholds. There was substantial uncertainty around these estimates in probabilistic sensitivity analysis, justifying future research to identify subgroups for whom each of these approaches may definitively be cost-effective.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gabapentin repurposing for glioblastoma therapy: Real-world data analyses augmented by use of active comparators.","authors":"Christine Ann Pittman Ballard, Kevin M Goff, Mallika P Patel, Kyle M Walsh, Michelle Monje, Quinn T Ostrom","doi":"10.1101/2025.09.24.25335799","DOIUrl":"https://doi.org/10.1101/2025.09.24.25335799","url":null,"abstract":"<p><p>Glioblastoma 'hijacks' neuronal pathways to drive tumor growth, and drugs affecting the function of these pathways may potentiate survival gains. Recent studies have suggested clinical benefits with post-diagnostic use of gabapentin. We assessed the impact of taking gabapentin after glioblastoma diagnosis utilizing an active comparator model in a population-based dataset of older adults in the United States. We leveraged a cohort of glioblastoma patients >65 years old who received resection, radiation, and temozolomide from the Surveillance, Epidemiology and End Results data paired with Medicare claims. Those receiving post-diagnostic gabapentin (TMZ+G) were compared to those receiving standard of care treatment only (TMZ), and two active comparators (duloxetine [TMZ+D], and levetiracetam [TMZ+L]). Association between medication use and overall survival was assessed using cox proportional hazards models adjusted for known prognostic factors. Out of 2,494 individuals, 797 (32%) received TMZ, 146 (5.9%) received TMZ+G, 38 (1.5%) received TMZ+D, and 1,513 (60.7%) received TMZ+L. Median survival among those receiving TMZ (10 months) as compared to all other groups (TMZ+G=16.3 months, TMZ+D=16 months; TMZ+L=13.0 months). TMZ+G was associated with 47% decrease in hazard of death (p<0.001) compared to TMZ, and a 32% decrease (p<0.001) compared to TMZ+L. Women had a 43% decrease in hazard of death (p<0.001) in TMZ+G as compared to TMZ+L, while this difference was non-significant in men (p=0.204). These results show survival benefit associated with gabapentin and supports ongoing work therapeutically targeting neuron-glioma interactions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Comprehensive Genetic Factors, Pathways, and Shared Genetic Architecture of Putamen Volume in Adolescent Cohort.","authors":"Abanish Singh, Jonathan Posner","doi":"10.1101/2025.09.24.25336566","DOIUrl":"https://doi.org/10.1101/2025.09.24.25336566","url":null,"abstract":"<p><p>The putamen plays a key role in motor control, learning, and cognition, with abnormal putamen volumes associated with neuropsychiatric disorders. Using data from the ABCD study, we performed a genome wide association study (GWAS) of putamen volumes, followed by replication and pathway enrichment analyses. We next evaluated the shared genetic architecture of putamen volume and neuropsychiatric disorders-including depression, schizophrenia, Parkinson's, ADHD, bipolar, and OCD- using SNP associations from this and prior GWASs. We identified 199 genome-wide significant SNP associations in White participants. Most identified SNPs were in gene regulatory regions and in the neuronal growth-linked genes, <i>DCC</i> and <i>DSCAM</i> . Sixteen of the most significant associations observed in Whites were replicated in non-White participants. Twenty-one SNPs from prior GWASs of putamen volumes were also replicated in our ABCD GWAS analysis, including five of the top eight SNPs. There was considerable genetic heterogeneity between White and non-White participants in putamen-linked SNPs with significant differences between the minor allele frequencies across the two groups (Wilcoxon rank-sum test Exact prob < 0.0001). We identified a key pathway ( <i>REACTOME_DSCAM_INTERACTIONS)</i> associated with putamen volume that involves <i>DSCAM</i> gene, netrin-1 protein and/or <i>DCC</i> gene. In addition, 28 unique SNPs from prior GWASs of neuropsychiatric disorders were strongly associated with putamen volume at Bonferroni-corrected significance, while 40 SNPs shared by at least three disorders were associated with putamen volume at a 0.05 threshold. Our findings provide deeper insights into the shared genetic architecture and cross-population differences in genetic associations of putamen volume.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-outcome Prediction of Post-Ischemic Stroke Epilepsy and Mortality Using Multimodal Quantitative Biomarkers.","authors":"Yilun Chen, Alexandria L Soto, Tejaswi D Sudhakar, Adeel Zubair, Haoqi Sun, Jin Jing, Wendong Ge, Lucas Loman, Adithya Sivaraju, Nils Petersen, Lawrence J Hirsch, Hal Blumenfeld, Sahar F Zafar, Aaron F Struck, Kevin N Sheth, Emily J Gilmore, M Brandon Westover, Jennifer A Kim","doi":"10.1101/2025.09.22.25335736","DOIUrl":"https://doi.org/10.1101/2025.09.22.25335736","url":null,"abstract":"<p><strong>Background and objectives: </strong>Post-ischemic stroke epilepsy (PISE) reduces quality of life, and early risk prediction can guide prevention strategies and anti-epileptogenesis treatment trials. Stroke severity predicts both PISE and mortality, and ignoring mortality can overestimate epilepsy risk. We sought to enhance PISE risk stratification by modeling death as a competing outcome, integrating quantitative clinical, neuroimaging, and electroencephalography (EEG) biomarkers to distinguish shared and distinct predictors of epilepsy and mortality.</p><p><strong>Methods: </strong>We developed a PISE prediction model using retrospective data from Yale-New Haven Hospital. The training cohort included patients from 2014-2020; the testing cohort from 2021-2022. Eligible patients were adults with acute ischemic stroke who underwent neuroimaging and EEG monitoring <7 days post-stroke and had follow-up >7 days.</p><p><strong>Results: </strong>Of 280 patients, 53 developed PISE first, 104 died first, and the rest were censored. Quantitative PISE biomarkers included greater 72h stroke severity (HR _Δ3 [95%CI], 1.2 [1.1-1.4]), infarct volume (HR _Δ10mL , 1.06 [1.04-1.08]), EEG epileptiform abnormality burden (HR _Δ10% , 1.2 [1.1-1.3]), and EEG power asymmetries (HR _Δ10% , 2.0 [1.4-2.9]). Death predictors included older age (HR _Δ10years , 1.7 [1.4-2.0]), worse pre-stroke functional status (HR, 1.4 [1.2-1.7]), atrial fibrillation history (HR, 2.4 [1.6-3.7]), cardioembolism etiology (HR, 1.9 [1.2-3.0]), anterior cerebral artery involvement (HR, 2.2 [1.2-3.7]), and greater EEG global theta-band powers (HR _Δ10µV , 6.2 [2.3-17]). Our model, CRIME _PISE , integrating these features, allows prediction of PISE-first and death-first risk scores with AUC of 0.72 (95%CI, 0.60-0.83) and 0.79 (0.72-0.85), respectively. Compared with the benchmark SeLECT model, CRIME _PISE better predicted PISE in patients with ≥4 SeLECT points (AUC, 0.72 vs 0.58) but not those with <4 points (AUC, 0.33 vs 0.52). In the testing cohort, CRIME _PISE identified a more selective group (n=18 vs 44 per SeLECT) with a higher PISE rate (39% vs 20%) and a lower mortality rate (22% vs 45%).</p><p><strong>Discussion: </strong>CRIME _PISE enhances PISE prediction by accounting for mortality as a competing outcome and incorporating multimodal quantitative biomarkers. Because its benefits over SeLECT are most pronounced in high-risk patients, a two-stage approach-SeLECT screening followed by CRIME _PISE in SeLECT-positive cases-may better target candidates for anti-epileptogenesis trials by prioritizing patients likely to survive long-term and develop epilepsy.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}