medRxiv : the preprint server for health sciences最新文献

{"title":"Posttraumatic Stress Disorder Epigenome-Wide Association Studies in the Million Veteran Program.","authors":"Sarah Beck, Daniel F Levey, Marco Galimberti, Cassie Overstreet, Jiarui Chen, Priya Gupta, Cecilia Dao, Bluma J Lesch, Janitza L Montalvo-Ortiz, Kelly M Harrington, J Michael Gaziano, John H Krystal, Renato Polimanti, Matthew J Girgenti, Murray B Stein, Joel Gelernter","doi":"10.64898/2026.09.04.26362177","DOIUrl":"10.64898/2026.09.04.26362177","url":null,"abstract":"<p><p>Genomic studies have improved our understanding of posttraumatic stress disorder (PTSD) biology. Epigenetic differences in DNA methylation can reflect environmental influences, which are critical in PTSD etiology, and may additionally differentiate between PTSD cases and controls or distinguish severity of PTSD symptoms. We conducted epigenome-wide association studies (EWAS) of PTSD in 22,141 subjects from the United States V.A. Million Veteran Program (MVP), using the PTSD Checklist (PCL-C), including 17,674 European ancestry (EUR), 3,430 African ancestry (AFR), and 1,037 admixed American descent (AMR) individuals. We evaluated the 17-item PCL-C and its symptom subdomains (re-experiencing, avoidance, and hyperarousal) and used our previously-reported algorithmically-defined PTSD diagnoses validated against clinical records. There were 9,413 total cases of Lifetime PTSD and 27,257 controls, with 5,184 cases and 19,382 controls in EUR, 3,095 cases and 6,240 controls in AFR, and 1,134 cases and 1,635 controls in AMR. We identified a total of 272 epigenome-wide-significant associated CpG sites across all PTSD traits, or 28 after adjusting for smoking status. We replicated 5 out of 11 CpG sites reported in a prior (Psychiatric Genomics Consortium) PTSD EWAS. There was significant enrichment of genes downregulated in somatostatin interneurons and of genes expressed in GABAergic interneurons. Regression analyses showed that PTSD case status was significantly correlated with accelerated DNA methylation aging. Contrary to previous PTSD EWAS findings, smoking status stratification suggested that the association between PTSD and methylation of the <i>AHRR</i> gene may be confounded by smoking status. This is the largest-scale PTSD EWAS in multiple ancestries and the first large PTSD EWAS on symptom severity. We replicate findings from previous EWAS and greatly extend knowledge of the epigenetics of PTSD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13622732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121443","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":"Haploinsufficiency, <i>de novo</i> and biallelic missense variants in <i>CSMD2</i> are associated with neurodevelopmental disorders.","authors":"Clara Pailler-Pradeau, Marianne Victoria Lemée, Caterina Cevallos, Francesca Mattioli, Jacqueline Chrast, Sissy Bassani, Hossein Darvish, Ginevra Zanni, Giovanna Stefania Colafati, Lorena Travaglini, Francesco Nicita, Shivarajan M Amudhavalli, Caitlin Lawson, Joseph G Gleeson, Isabella Stuewe, Liana Friedman, Maha S Zaki, Lauren Bell, Elise Boucher Brischoux, Paul Kuentz, Nico Fuhrmann, Victoria Lampkemeyer, Christian Netzer, Thomas Smol, Catherine Vincent-Delorme, Zafar Iqbal, Mathias Toft, Tarab Zehra, Sidra Kaleem Jafri, Ambrin Fatima, Mukhtar Ullah, Zainab Akhtar, Tayyaba Shan, Sabika Firasat, Saghar Ghasemi Firouzabadi, Abbas Tafakhori, Sarina Sharbatkhori, Faezeh Jamali, Maximilian Balbach, Friedhelm Hildebrandt, Emily O'Heir, Lynn Pais, Alba Sanchis-Juan, Michael E Talkowski, Quinten Waisfisz, Lotte Kleinendorst, Giovanna Ambrosini, Trisha Kuchta, Zoltan Kutalik, Nicolas Guex, Stylianos E Antonarakis, Muhammad Ansar, Christelle Golzio, Alexandre Reymond","doi":"10.64898/2026.09.24.26361611","DOIUrl":"10.64898/2026.09.24.26361611","url":null,"abstract":"<p><p>CUB and Sushi domains-containing CSMD proteins are involved in neuron development. Variants in the <i>CSMD1-3</i> paralogs were GWAS-associated with cognition, attention-deficit hyperactivity disorder (ADHD), schizophrenia and brain structure, suggesting that these genes could be linked to neurodevelopmental disorders (NDD). Indeed, rare biallelic variants in all three <i>CSMD</i> paralogs were recently associated with epilepsy, while rare biallelic variants in <i>CSMD1</i> were also linked with intellectual disability and cortical malformations. We identified nine individuals from eight families carrying <i>CSMD2</i> biallelic missense variants in developmental delay/intellectual disability cohorts. Affected individuals presented with autism spectrum disorder (ASD), ADHD and brain anomalies. Consistent with gnomAD metrics that suggest <i>CSMD2</i> haploinsufficiency, we also report two families segregating monoallelic <i>CSMD2</i> frameshift variants, which complement a described <i>de novo</i> truncation variant in an ASD proband. We concomitantly report two phenotypically overlapping individuals with <i>de novo CSMD2</i> missense variants and compare them to twelve <i>de novo CSMD2</i> cases identified in published trio analyses. UK Biobank analyses showed nominally significant enrichment of ADHD, ASD and neuroticism in volunteers carrying at least one rare <i>CSMD2</i> variant. <i>In silico</i> modelling and immunofluorescence assays showed that mutated residues in affected individuals with biallelic and <i>de novo</i> missense variants are clustering in two regions and that the encoded proteins showed impaired membrane localization and an increased cytoplasmic aggregation. Zebrafish crispant larvae for the orthologous <i>csmd2</i> presented with microcephaly, smaller cerebellum, and reduced Purkinje cell size. Larvae also displayed decreased swimming velocity, diminished connectivity between the optic tecta, and abnormal peripheral neuronal branching. We demonstrate that rare, likely pathogenic variants in <i>CSMD2</i> are associated with both autosomal recessive and dominant forms of NDD further substantiating the functional significance of CSMD paralogs in neurogenesis/synapse formation.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172275","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":"Urinary 27-nor-5β-cholestane-3α,7α,12α,24R,25S-pentol glucuronide as a biomarker of non-small cell lung cancer in never-smokers: two independent case-control studies.","authors":"Seyon Chung, Huaitian Liu, Mohammed Khan, Tanvi S Patel, Burchelle Blackman, Rolf E Swenson, Sharon R Pine, Frank J Gonzalez, Curtis C Harris, Daxesh P Patel","doi":"10.64898/2026.07.27.26359037","DOIUrl":"10.64898/2026.07.27.26359037","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer in never-smokers is excluded from low-dose computed tomography screening because eligibility is defined by smoking history, and no non-invasive marker is available to select never-smokers for imaging. We evaluated urinary 27-nor-5β-cholestane-3α,7α,12α,24 <i>R</i> ,25 <i>S</i> -pentol glucuronide (CPG), a structurally authenticated bile alcohol glucuronide, as a marker of non-small cell lung cancer (NSCLC) in never-smokers.</p><p><strong>Methods: </strong>CPG was quantified by ultra-performance liquid chromatography-tandem mass spectrometry against a synthetic standard in urine from two independent case-control studies (661 cases, 690 controls). The primary analyses compared never-smoker cases directly with never-smoker controls (NCI-Maryland, 114 cases and 203 controls; Colorado, 80 cases and 108 controls) by logistic regression adjusted for age, sex and race, for all stages and by stage, pooled across studies. Survival among never-smoker cases was analyzed by Kaplan-Meier and Cox regression. Analyses of all participants and of tumor transcriptomes were secondary.</p><p><strong>Results: </strong>CPG was higher in never-smoker cases than in never-smoker controls in both studies (both P < 0.001). Adjusted odds ratios (OR) per standard deviation were near-identical across studies (1.83, 95% CI 1.32-2.54, and 1.81, 1.24-2.65; heterogeneity P = 0.96; pooled 1.82, 1.43-2.31). Elevation was present in stage I-II disease (pooled OR 1.38, 1.04-1.82) and greater in stage III-IV disease (2.27, 1.66-3.12). Single-marker discrimination was modest (area under the curve 0.63 and 0.70). High CPG was associated with shorter overall survival among never-smoker cases in NCI-Maryland independently of stage (hazard ratio 2.56, 1.58-4.14), and in the same direction in Colorado (1.63, 0.72-3.69). Among all participants, CPG was also higher in cases (pooled OR 1.61, 1.42-1.82), without effect modification by smoking, and remained associated after mutual adjustment for creatine riboside and <i>N</i> -acetylneuraminic acid. Tumors from patients with high urinary CPG showed enrichment of xenobiotic-metabolism, aryl hydrocarbon receptor/cytochrome P450 and Nrf2 programs.</p><p><strong>Conclusions: </strong>Urinary CPG is reproducibly elevated in never-smokers with NSCLC compared with never-smoker controls, including in early-stage disease, in two independent studies. These phase 2 data support evaluation of CPG within multimarker panels in pre-diagnostic urine from never-smokers, a population with no current screening pathway.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13484339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148804053","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":"Daily Exceedance of World Health Organization Air Pollutant Guidelines and Cognitive Aging.","authors":"Mikaela Bloomberg, Giorgio Di Gessa, Shaun Scholes, Antonio Gasparrini, Arturo de la Cruz Libardi, Andrew Steptoe, Paola Zaninotto","doi":"10.64898/2026.09.23.26363787","DOIUrl":"10.64898/2026.09.23.26363787","url":null,"abstract":"<p><strong>Importance: </strong>Long-term exposure to higher average air pollutant concentrations is associated with poorer cognitive health, but annual averages can obscure substantial differences in dayto-day exposure. Whether recurrent high pollution days are associated with long-term cognitive aging trajectories among people with similar overall air pollution exposure is unclear.</p><p><strong>Objective: </strong>To determine whether the annual number of days exceeding World Health Organization daily guideline values for nitrogen dioxide (NO₂) and particulate matter (PM_2.5 and PM₁₀) is associated with subsequent cognitive decline after accounting for annual mean air pollutant exposure.</p><p><strong>Design: </strong>Prospective cohort study using data from waves 1-10 (2002-03 to 2021-23) of the English Longitudinal Study of Ageing.</p><p><strong>Setting: </strong>Population-based cohort of community-dwelling adults in England.</p><p><strong>Participants: </strong>12,235 adults aged 50+ years at analytic baseline.</p><p><strong>Exposures: </strong>Number of days exceeding World Health Organization daily guideline values ('exceedance days') for NO₂, PM_2.5, and PM₁₀, derived from residence-linked environmental estimates during the calendar year preceding the analytic baseline.</p><p><strong>Main outcomes and measures: </strong>Baseline cognitive performance and model-estimated 14-year cognitive decline (corresponding to the 75th percentile of follow-up duration) in episodic memory and verbal fluency.</p><p><strong>Results: </strong>Exceedance days were not associated with baseline memory or verbal fluency after adjustment for annual mean air pollutant exposure. More NO₂ exceedance days were associated with faster cognitive decline: comparing the 75th percentile with the median of NO₂ exceedance days, the difference in 14-year decline was -0.09 SD (95% CI, -0.17 to -0.01; p = 0.02) for memory and -0.10 SD (95% CI, -0.19 to 0.00; p = 0.04) for fluency. PM_2.5 and PM₁₀ exceedance days were not associated with cognitive decline.</p><p><strong>Conclusions and relevance: </strong>In this cohort study of older adults, a higher number of NO₂ exceedance days was associated with faster subsequent cognitive decline after adjustment for annual mean air pollutant exposure. This suggests that daily exposure to high NO₂ concentrations may be related to accelerated cognitive aging even when offset by lower exposure on other days, potentially providing a new rationale for identifying and prioritizing areas with recurrent high NO₂ exposure and the local emission sources contributing to it.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170987","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":"When Cuts Cost More: Projected Fiscal Impact of Eliminating the AIDS Drug Assistance Program in 30 US States.","authors":"Ryan M Forster, Melissa Schnure, Ruchita Balasubramanian, Joyce L Jones, Emily P Hyle, Scott Batey, Keri N Althoff, Kelly Gebo, David W Dowdy, Maunank Shah, Anthony T Fojo, Parastu Kasaie","doi":"10.64898/2026.07.27.26359045","DOIUrl":"10.64898/2026.07.27.26359045","url":null,"abstract":"<p><strong>Background: </strong>The AIDS Drug Assistance Program (ADAP) supports antiretroviral therapy for low-income people with HIV. We assessed whether ADAP savings would offset additional HIV care costs resulting from new infections.</p><p><strong>Methods: </strong>Using the Joint HIV Epidemiologic and Economic Model calibrated to 30 US states and the District of Columbia, we compared continued 2025 ADAP coverage with elimination beginning Jan-2026. We projected excess HIV infections and care costs through 2035 under three cost-scenarios. Projected costs were limited to HIV care costs attributable to excess incident infections that would results from eliminating ADAP. The primary outcome was the Net Cost to Expenditure Ratio (NCER), defined as healthcare-system costs minus ADAP expenditure, relative to ADAP expenditure by 2035.</p><p><strong>Results: </strong>Across the modeled US jurisdictions, ADAP elimination was projected to result in a median of 143,347 additional HIV incident cases, generating $11.24 billion in HIV care costs through 2035. Compared with $6.58 billion in ADAP spending, this resulted in $4.66 billion in net additional costs (NCER=0.71). For every $1 in ADAP spending avoided, the healthcare system incurred $1.71 in downstream HIV care costs, a net increase of $0.71. This pattern was strongest in states with high baseline ADAP coverage and more rural HIV populations, many of which were Medicaid non-expansion states in the South, with substantial variation in NCER across jurisdictions (3.79 in Missouri to -0.97 in the District of Columbia).</p><p><strong>Conclusions: </strong>Eliminating ADAP would be medically and fiscally counterproductive, increasing HIV burden and generating healthcare costs that would exceed program savings within seven years.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13484327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803769","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":"AI-Enabled Echocardiography Identifies Prominent Epicardial Adipose Tissue Associated With an Adverse Cardiometabolic Profile.","authors":"Arya Aminorroaya, Andreas Coppi, Robert L McNamara, Joao A C Lima, Harlan M Krumholz, Charalambos Antoniades, Rohan Khera, Evangelos K Oikonomou","doi":"10.64898/2026.07.22.26358690","DOIUrl":"10.64898/2026.07.22.26358690","url":null,"abstract":"<p><strong>Background: </strong>Excess epicardial adipose tissue (EAT) is associated with cardiovascular-kidney-metabolic (CKM) dysfunction, but its assessment has traditionally required advanced imaging.</p><p><strong>Objectives: </strong>We investigated whether AI-enabled echocardiography could characterize epicardial adiposity and identify residual cardiometabolic risk beyond body mass index (BMI).</p><p><strong>Methods: </strong>We developed <i>PanAdipo</i>, a video-based deep learning model in 1,114,441 videos from 28,797 studies across the Yale-New Haven Health System (YNHHS; 2016-2022), using report-derived expert reader labels of prominent EAT (2.3% of studies). <i>PanAdipo</i> was evaluated in five cohorts: a <i>temporally</i> distinct YNHHS transthoracic echocardiography (TTE) set (n=4,588 patients contributing 5,130 studies), an emergency department point-of-care ultrasound (POCUS) cohort (n=10,957), the geographically distinct MIMIC-IV dataset (n=4,549), the community-based Multi-Ethnic Study of Atherosclerosis (MESA Exam 6, n=2,740), and in held-out YNHHS patients with paired coronary CT angiography within 12 months (n=5,167). Analyses examined discrimination of the report label and of CT-defined high indexed EAT volume, correlation with paired cardiac CT phenotypes, and BMI-adjusted associations with cardiometabolic biomarkers and newly documented metabolic disease.</p><p><strong>Results: </strong>In the held-out health system test set, PanAdipo identified prominent EAT documented in clinical reports with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI, 0.82-0.91) across all views and of up to 0.93 when combining apical 4-chamber and parasternal views. Against paired CT-derived measurements, PanAdipo discriminated age- and sex-specific high EAT (EAT/heart volume ≥95th percentile) with AUROCs of 0.91 to 0.95 across age-sex groups and correlated more strongly with indexed EAT volume (ρ=0.76) than with BMI (ρ=0.41, all P<0.001); PanAdipo alone explained 53% of indexed EAT volume variance, versus 23% for age, sex, and BMI combined. In MESA, higher scores were associated with an adverse metabolic profile (higher HOMA-IR [β=0.17 per SD; 95% CI, 0.11-0.22]) after adjustment for age, sex, and BMI. In health system TTE and POCUS cohorts, higher scores were associated with newly documented MASLD/MASH (BMI-adjusted HR_pooled 1.31 [1.03-1.67] per SD of log[PanAdipo]) and hyperlipidemia (1.11 [1.04-1.18]).</p><p><strong>Conclusions: </strong>AI-enabled echocardiography provides a scalable digital biomarker that characterizes prominent epicardial adiposity and is associated with an adverse cardiometabolic profile, highlighting a role for echocardiography in metabolic risk stratification.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13419655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148650228","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":"Documenting HIV service delivery and adoption of evidence-based practices in HIV care programs: A protocol for a cross-sectional survey of HIV clinics participating in the International epidemiology Databases to Evaluate AIDS (IeDEA).","authors":"Ellen Brazier, Fernanda Maruri, Stephany N Duda, Kara Wools-Kaloustian, Aimee Freeman, Beverly Musick, Sophia Arabadjis, Marie Ballif, Nathalie Verónica Fernández Villalobos, Mark H Kuniholm, Kathryn E Lancaster, Sita Lujintanon, Angela M Parcesepe, Rachael A Pellegrino, Ana Fernanda Ramos Menchelli, Jeremy Ross, Jonathan Ross, Aggrey Semeere, Denis Nash","doi":"10.64898/2026.09.16.26363245","DOIUrl":"10.64898/2026.09.16.26363245","url":null,"abstract":"<p><strong>Introduction: </strong>HIV care and treatment programs around the world continue to evolve in response to changes in clinical guidelines, evidence-based practices, domestic and donor funding for the HIV response, new technological developments, and changing weather patterns. Since 2009, the International epidemiology Databases to Evaluate AIDS (IeDEA) research consortium has conducted periodic surveys to document the characteristics of participating clinics and the availability of HIV-related services across diverse settings-information that provides important context for understanding variations and trends in HIV care outcomes. This paper describes the protocol for IeDEA's 2026 site assessment survey, launched in August 2026.</p><p><strong>Methods and analysis: </strong>This cross-sectional descriptive study aims to document HIV-related services and practices among clinics in 42 countries. The survey explores the characteristics and services provided at HIV care and treatment sites participating in IeDEA in 2026, along with real-world adoption and implementation of evidence-based service delivery strategies for people living with or at risk of HIV. Designed for self-administration, the survey questionnaire was developed through two complementary processes: a review of questions and data collected through IeDEA's prior consortium-wide surveys and an open call to IeDEA investigators for new survey content to advance a timely implementation science agenda relevant to the global HIV community. Survey materials and links to an online REDCap questionnaire will be distributed to 235 eligible clinics across IeDEA in September 2026, with a deadline of November 30, 2026, for completion. Planned analyses will examine the following topics: HIV care amidst funding constraints; the roll-out of differentiated service delivery models; pre-exposure HIV prophylaxis; long-acting injectable antiretroviral therapy (ART); prevention, screening and/or treatment services for viral hepatitis, mental health and substance use disorders, cardiovascular disease, and cancers among PLHIV; the integration of HIV care with other health services; and clinic vulnerability to extreme weather events.</p><p><strong>Ethics and dissemination: </strong>A \"non-human subjects\" research designation was determined by the Vanderbilt University Medical Center Human Research Protections Program. Survey findings will be shared with local partners and stakeholders across IeDEA, disseminated at regional and global conferences, and published in peer-reviewed journals.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149032464","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":"Advancing genetic pathogenicity prediction with three-dimensional proteoform-phenotype analysis.","authors":"Young Joo Sun, Gabriel Velez, Angela Li, Aarushi Kumar, Jennifer T Vu, Claudia Phillips, Ditte K Rasmussen, Jin Kyun Oh, Mauricio G S Costa, Stephen H Tsang, Yang Sun, Alexander G Bassuk, Vinit B Mahajan","doi":"10.64898/2026.10.07.26364649","DOIUrl":"10.64898/2026.10.07.26364649","url":null,"abstract":"<p><p>Ascertaining the pathogenicity and clinical relevance of genetic mutations is a longstanding challenge across human disease. This is particularly relevant for genes with many variants of unknown significance (VUS), such as <i>PRPH2</i>-retinopathy, where complex variable phenotype patterns and limited genotype correlations hinder application of precision-medicine therapies. Recent AI-based pathogenicity tools, while powerful, may be limited by insufficient mechanistic or phenotypic training data. We established a three-dimensional proteoform-phenotype analysis framework by combining AI-generated protein structural models with clinical genomics data, in which expert consensus adjudicates model outputs through a human-in-the-loop AI approach, to evaluate 46 curated pathogenic missense variants against a background VUS pool. The framework was prospectively validated using an independently evaluated clinical patient cohort. This analysis resolved spatial biophysical signatures corresponding to distinct clinical phenotypes (i.e., retinitis pigmentosa, macular dystrophy, and pattern dystrophy) as well as complex blended presentations. Leveraging these confirmed structural signatures, we prioritized high-risk VUS. This mechanism-resolved framework can be extended to other therapeutically actionable genes to identify novel causal variants and improve diagnosis, prognosis, and better select rare, eligible patients for emerging molecular gene therapy trials.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198212","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":"Identifying Family Relationships from Electronic Health Records: A Machine Learning Approach.","authors":"Abhinav Pundir, Andrew Hill, Michael G Kahn, Bethany M Kwan, Daniel M Lindberg, Shaun J Grannis, Titus K Schleyer, Lisa M Schilling, Sarah V Kautz, Toan C Ong","doi":"10.64898/2026.09.18.26363428","DOIUrl":"10.64898/2026.09.18.26363428","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To develop and evaluate machine learning methods for automated identification of family relationships from electronic health records (EHRs). We employed Random Forest classifiers to identify five relationship types: Mother-Child, Father-Child, Sibling-Sibling, Twin-Twin, and Partner-Partner, using a four-stage iterative refinement process to improve precision for patient-centered outcomes research (PCOR) and healthcare applications.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materials and methods: &lt;/strong&gt;We used two large-scale Indiana datasets: the Indiana Network for Patient Care (INPC), comprising approximately 15 million unique individuals across approximately 45 million medical records, and the Indiana Natality dataset (birth certificates, 1970-2024), which served as the gold standard. Positive cases were derived by linking verified relationships from Natality records to INPC using a shared Global Identifier. Negative cases were drawn from a three-tier blocking strategy combined with sliding window restriction and similarity scoring, which together reduced the comparison space from over 10&lt;sup&gt;17&lt;/sup&gt; potential pairs to approximately 121 million candidates. Five Random Forest classifiers underwent four-stage iterative refinement: initial training, feature removal for multicollinearity, feature engineering to address systematic errors, and training-data refinement restricted to relationship pairs with at least one shared contact feature.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The models achieved precision of 0.92 to 1.00, recall of 0.97 to 1.00, and F1 scores of 0.94 to 1.00 across all relationship types (Mother-Child 0.97, Father-Child 0.98, Sibling-Sibling 0.98, Twin-Twin 1.00, Partner-Partner 0.94). Between 15% and 78% of Natality-verified relationships lacked any shared contact information in INPC and were structurally undetectable by record linkage; restricting training and evaluation to linkable pairs improved precision for four of the five models, and training-data refinement improved F1-scores by a further 0.02-0.04 for the Mother-Child, Father-Child, and Sibling models. High-confidence predictions (probability ≥ 0.9) captured 77-99% of true positives. Age difference was the primary predictor for parent-child and twin relationships, while phone number similarity was most important for siblings.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;The framework identifies family relationships from standard demographic fields available in most EHR systems. The iterative refinement approach shows how systematic error analysis can guide methodological improvements. Training-data refinement addresses a constraint in EHR-based family linkage: not all verified biological relationships have overlapping demographic footprints in healthcare data. Unlike rule-based approaches, the framework provides probability scores that enable configurable deployment thresholds.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The Random Forest models demonstrate high performance suitable for","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13622321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121253","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":"Single-Dose Suprachoroidal AXT107 in Neovascular Age-Related Macular Degeneration: The Phase 1/2a DISCOVER Trial.","authors":"Niranjan B Pandey, Adam C Mirando, Thomas J Robinson, David R P Almeida, Sabin Dang, David R Lally, William Z Bridges, Peter A Campochiaro, Aleksander S Popel, Jordan J Green","doi":"10.64898/2026.09.19.26363031","DOIUrl":"10.64898/2026.09.19.26363031","url":null,"abstract":"<p><p>Frequent injections remain a substantial burden in the treatment of neovascular age-related macular degeneration (nAMD). AXT107 (gersizangitide) is a long-acting, integrin-disrupting peptide designed for suprachoroidal administration. In the phase 1/2a, open-label DISCOVER trial, 15 participants with active nAMD received a single suprachoroidal injection of AXT107 microparticles at 0.125, 0.25, or 0.5 mg and were followed for 40 weeks. Safety and tolerability were the primary outcomes; visual acuity, retinal thickness, and time to protocol-specified rescue anti-vascular endothelial growth factor treatment were exploratory outcomes. No AXT107-related serious adverse events, clinically significant intraocular inflammation, or sustained intraocular pressure elevations were observed. Fourteen eyes met the protocol-specified baseline imaging criterion for efficacy analyses. Among these eyes, two treatment-experienced eyes completed 40 weeks without protocol-specified rescue, and a third first received protocol-specified rescue at week 36. Anatomical improvements were observed in at least one eye in each dose cohort, although responses varied. A single suprachoroidal injection of AXT107 was well tolerated in this small first-in-human study. The exploratory findings warrant evaluation in a controlled trial.</p><p><strong>One sentence summary: </strong>Suprachoroidal AXT107 was well tolerated, with some eyes remaining free of protocol-specified rescue for up to 40 weeks.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13622332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121483","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}