medRxiv : the preprint server for health sciences最新文献

{"title":"Leveraging Stacked Classifiers for Multi-task Executive Function in Schizophrenia Yields Diagnostic and Prognostic Insights.","authors":"Tongyi Zhang, Xin Zhao, B T Thomas Yeo, Xiaoning Huo, Simon B Eickhoff, Ji Chen","doi":"10.1101/2024.12.05.24318587","DOIUrl":"10.1101/2024.12.05.24318587","url":null,"abstract":"<p><p>Cognitive impairment is a central characteristic of schizophrenia. Executive functioning (EF) impairments are often seen in mental disorders, particularly schizophrenia, where they relate to adverse outcomes. As a heterogeneous construct, how specifically each dimension of EF to characterize the diagnostic and prognostic aspects of schizophrenia remains opaque. We used classification models with a stacking approach on systematically measured EFs to discriminate 195 patients with schizophrenia from healthy individuals. Baseline EF measurements were moreover employed to predict symptomatically remitted or non-remitted prognostic subgroups. EF feature importance was determined at the group-level and the ensuing individual importance scores were associated with four symptom dimensions. EF assessments of inhibitory control (interference and response inhibitions), followed by working memory, evidently predicted schizophrenia diagnosis (area under the curve [AUC]=0.87) and remission status (AUC=0.81). The models highlighted the importance of interference inhibition or working memory updating in accurately identifying individuals with schizophrenia or those in remission. These identified patients had high-level negative symptoms at baseline and those who remitted showed milder cognitive symptoms at follow-up, without differences in baseline EF or symptom severity compared to non-remitted patients. Our work indicates that impairments in specific EF dimensions in schizophrenia are differentially linked to individual symptom-load and prognostic outcomes. Thus, assessments and models based on EF may be a promising tool that can aid in the clinical evaluation of this disorder.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831607","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":"Uncovering Phenotypic Expansion in AXIN2-Related Disorders through Precision Animal Modeling.","authors":"Nathalie M Aceves-Ewing, Denise G Lanza, Paul C Marcogliese, Di Lu, Chih-Wei Hsu, Matthew Gonzalez, Audrey E Christiansen, Tara L Rasmussen, Alex J Ho, Angelina Gaspero, John Seavitt, Mary E Dickinson, Bo Yuan, Brian J Shayota, Stephanie Pachter, Xiaolin Hu, Debra Lynn Day-Salvatore, Laura Mackay, Oguz Kanca, Michael F Wangler, Lorraine Potocki, Jill A Rosenfeld, Richard Alan Lewis, Hsiao-Tuan Chao, Brendan Lee, Sukyeong Lee, Shinya Yamamoto, Hugo J Bellen, Lindsay C Burrage, Jason D Heaney","doi":"10.1101/2024.12.05.24318524","DOIUrl":"10.1101/2024.12.05.24318524","url":null,"abstract":"<p><p>Heterozygous pathogenic variants in <i>AXIN2</i> are associated with oligodontia-colorectal cancer syndrome (ODCRCS), a disorder characterized by oligodontia, colorectal cancer, and in some cases, sparse hair and eyebrows. We have identified four individuals with one of two <i>de novo</i> , heterozygous variants (NM_004655.4:c.196G>A, p.(Glu66Lys) and c.199G>T, p.(Gly67Arg)) in <i>AXIN2</i> whose presentations expand the phenotype of AXIN2-related disorders. In addition to ODCRCS features, these individuals have global developmental delay, microcephaly, and limb, ophthalmologic, and renal abnormalities. Structural modeling of these variants suggests that they disrupt AXIN2 binding to tankyrase, which regulates AXIN2 levels through PARsylation and subsequent proteasomal degradation. To test whether these variants produce a phenotype <i>in vivo</i> , we utilized an innovative prime editing N1 screen to phenotype heterozygous (p.E66K) mouse embryos, which were perinatal lethal with short palate and skeletal abnormalities, contrary to published viable <i>Axin2</i> null mouse models. Modeling of the p.E66K variant in the <i>Drosophila</i> wing revealed gain-of-function activity compared to reference AXIN2. However, the variant showed loss-of-function activity in the fly eye compared to reference AXIN2, suggesting that the mechanism by which p.E66K affects AXIN2 function is cell context-dependent. Together, our studies in humans, mice, and flies demonstrate that specific variants in the tankyrase-binding domain of AXIN2 are pathogenic, leading to phenotypic expansion with context-dependent effects on AXIN2 function and WNT signaling. Moreover, the modeling strategies used to demonstrate variant pathogenicity may be beneficial for the resolution of other <i>de novo</i> heterozygous variants of uncertain significance associated with congenital anomalies in humans.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831619","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":"Efficient multi-phenotype genome-wide analysis identifies genetic associations for unsupervised deep-learning-derived high-dimensional brain imaging phenotypes.","authors":"Bohong Guo, Ziqian Xie, Wei He, Sheikh Muhammad Saiful Islam, Assaf Gottlieb, Han Chen, Degui Zhi","doi":"10.1101/2024.12.06.24318618","DOIUrl":"10.1101/2024.12.06.24318618","url":null,"abstract":"<p><p>Brain imaging is a high-content modality that offers dense insights into the structure and pathology of the brain. Existing genetic association studies of brain imaging, typically focusing on a number of individual image-derived phenotypes (IDPs), have successfully identified many genetic loci. Previously, we have created a 128-dimensional Unsupervised Deep learning derived Imaging Phenotypes (UDIPs), and identified multiple loci from single-phenotype genome-wide association studies (GWAS) for individual UDIP dimensions, using data from the UK Biobank (UKB). However, this approach may miss genetic associations where one single nucleotide polymorphism (SNP) is moderately associated with multiple UDIP dimensions. Here, we present Joint Analysis of multi-phenotype GWAS (JAGWAS), a new tool that can efficiently calculate multivariate association statistics using single-phenotype summary statistics for hundreds of phenotypes. When applied to UDIPs of T1 and T2 brain magnetic resonance imaging (MRI) on discovery and replication cohorts from the UKB, JAGWAS identified 195/168 independently replicated genomic loci for T1/T2, 6 times more than those from the single-phenotype GWAS. The replicated loci were mapped into 555/494 genes, and 217/188 genes overlapped with the expression quantitative trait loci (eQTL) of brain tissues. Gene enrichment analysis indicated that the genes mapped are closely related to neurobiological functions. Our results suggested that multi-phenotype GWAS is a powerful approach for genetic discovery using high-dimensional UDIPs.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831499","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":"Leveraging functional annotations to map rare variants associated with Alzheimer's disease with gruyere.","authors":"Anjali Das, Chirag Lakhani, Chloé Terwagne, Jui-Shan T Lin, Tatsuhiko Naito, Towfique Raj, David A Knowles","doi":"10.1101/2024.12.06.24318577","DOIUrl":"10.1101/2024.12.06.24318577","url":null,"abstract":"<p><p>The increasing availability of whole-genome sequencing (WGS) has begun to elucidate the contribution of rare variants (RVs), both coding and non-coding, to complex disease. Multiple RV association tests are available to study the relationship between genotype and phenotype, but most are restricted to per-gene models and do not fully leverage the availability of variant-level functional annotations. We propose Genome-wide Rare Variant EnRichment Evaluation (gruyere), a Bayesian probabilistic model that complements existing methods by learning global, trait-specific weights for functional annotations to improve variant prioritization. We apply gruyere to WGS data from the Alzheimer's Disease (AD) Sequencing Project, consisting of 7,966 cases and 13,412 controls, to identify AD-associated genes and annotations. Growing evidence suggests that disruption of microglial regulation is a key contributor to AD risk, yet existing methods have not had sufficient power to examine rare non-coding effects that incorporate such cell-type specific information. To address this gap, we 1) use predicted enhancer and promoter regions in microglia and other potentially relevant cell types (oligodendrocytes, astrocytes, and neurons) to define per-gene non-coding RV test sets and 2) include cell-type specific variant effect predictions (VEPs) as functional annotations. gruyere identifies 15 significant genetic associations not detected by other RV methods and finds deep learning-based VEPs for splicing, transcription factor binding, and chromatin state are highly predictive of functional non-coding RVs. Our study establishes a novel and robust framework incorporating functional annotations, coding RVs, and cell-type associated non-coding RVs, to perform genome-wide association tests, uncovering AD-relevant genes and annotations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831605","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":"Plasma proteomics for novel biomarker discovery in childhood tuberculosis.","authors":"Andrea Fossati, Peter Wambi, Devan Jaganath, Roger Calderon, Robert Castro, Alexander Mohapatra, Justin McKetney, Juaneta Luiz, Rutuja Nerurkar, Esin Nkereuwem, Molly F Franke, Zaynab Mousavian, Jeffrey M Collins, George B Sigal, Mark R Segal, Beate Kampman, Eric Wobudeya, Adithya Cattamanchi, Joel D Ernst, Heather J Zar, Danielle L Swaney","doi":"10.1101/2024.12.05.24318340","DOIUrl":"10.1101/2024.12.05.24318340","url":null,"abstract":"<p><p>Failure to rapidly diagnose tuberculosis disease (TB) and initiate treatment is a driving factor of TB as a leading cause of death in children. Current TB diagnostic assays have poor performance in children, and identifying novel non-sputum-based TB biomarkers to improve pediatric TB diagnosis is a global priority. We sought to develop a plasma biosignature for TB by probing the plasma proteome of 511 children stratified by TB diagnostic classification and HIV status from sites in four low- and middle-income countries, using high-throughput data-independent acquisition mass-spectrometry (DIA-PASEF-MS). We identified 47 proteins differentially regulated (BH adjusted p-values < 1%) between children with microbiologically confirmed TB and children with non-TB respiratory diseases (Unlikely TB). We further employed machine learning to derive three parsimonious biosignatures encompassing 4, 5, or 6 proteins that achieved AUCs of 0.86-0.88 all of which exceeded the minimum WHO target product profile accuracy thresholds for a TB screening test (70% specificity at 90% sensitivity, PPV 0.65-0.74, NPV 0.92-0.95). This work provides insights into the unique host response in pediatric TB disease, as well as a non-sputum biosignature that could reduce delays in TB diagnosis and improve detection and management of TB in children worldwide.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831047","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":"A Titin Missense Variant Causes Atrial Fibrillation.","authors":"Mahmud Arif Pavel, Hanna Chen, Michael Hill, Arvind Sridhar, Miles Barney, Jaime DeSantiago, Asia Owais, Shashank Sandu, Faisal A Darbar, Aylin Ornelas-Loredo, Bahaa Al-Azzam, Brandon Chalazan, Jalees Rehman, Dawood Darbar","doi":"10.1101/2024.12.06.24318402","DOIUrl":"10.1101/2024.12.06.24318402","url":null,"abstract":"<p><p>Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes such as <i>TTN</i> have also been implicated in AF pathogenesis partly by the development of an atrial myopathy, but the underlying mechanisms are poorly understood. While <i>TTN</i> truncating variants (<i>TTN</i>tvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear. We report that rare <i>TTN</i>mvs are associated with adverse clinical outcomes in AF patients and we have identified a mechanism by which a <i>TTN</i>mv (T32756I) causes AF. Modeling the <i>TTN</i>-T32756I variant using human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) revealed that the mutant cells display aberrant contractility, increased activity of a cardiac potassium channel (KCNQ1, Kv7.1), and dysregulated calcium homeostasis without compromising the sarcomeric integrity of the atrial cardiomyocytes. We also show that a titin-binding protein, the Four-and-a-Half Lim domains 2 (FHL2), has increased binding with KCNQ1 and its modulatory subunit KCNE1 in the <i>TTN-</i>T32756I-iPSC-aCMs, enhancing the slow delayed rectifier potassium current (<i>I</i> _ks). Suppression of FHL2 in mutant iPSC-aCMs normalized the <i>I</i> _ks, supporting FHL2 as an <i>I</i> _ks modulator. Our findings demonstrate that a single amino acid change in titin not only affects function but also causes ion channel remodeling and AF. These findings emphasize the need for high-throughput screening to evaluate the pathogenicity of <i>TTN</i>mvs and establish a mechanistic link between titin, potassium ion channels, and sarcomeric proteins that may represent a novel therapeutic target.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831591","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":"Longitudinal Digital Phenotyping of Multiple Sclerosis Severity Using Passively Sensed Behaviors and Ecological Momentary Assessments.","authors":"Zongqi Xia, Prerna Chikersal, Shruthi Venkatesh, Elizabeth Walker, Anind Dey, Mayank Goel","doi":"10.1101/2024.11.02.24316647","DOIUrl":"10.1101/2024.11.02.24316647","url":null,"abstract":"<p><strong>Background: </strong>Longitudinal tracking of multiple sclerosis (MS) symptoms in an individual's own environment may improve self-monitoring and clinical management for people with MS (pwMS).</p><p><strong>Objective: </strong>We present a machine learning approach that enables longitudinal monitoring of clinically relevant patient-reported symptoms for pwMS by harnessing passively collected data from sensors in smartphones and fitness trackers.</p><p><strong>Methods: </strong>We divide the collected data into discrete periods for each patient. For each prediction period, we first extract patient-level behavioral features from the current period (action features) and the previous period (context features). Then, we apply a machine learning (ML) approach based on Support Vector Machine with Radial Bias Function Kernel and AdaBoost to predict the presence of depressive symptoms (every two weeks) and high global MS symptom burden, severe fatigue, and poor sleep quality (every four weeks).</p><p><strong>Results: </strong>Between November 16, 2019, and January 24, 2021, 104 pwMS (84.6% women, 93.3% non-Hispanic White, 44.0±11.8 years mean±SD age) from a clinic-based MS cohort completed 12-weeks of data collection, including a subset of 44 pwMS (88.6% women, 95.5% non-Hispanic White, 45.7±11.2 years) who completed 24-weeks of data collection. In total, we collected approximately 12,500 days of passive sensor and behavioral health data from the participants. Among the best-performing models with the least sensor data requirement, ML algorithm predicts depressive symptoms with an accuracy of 80.6% (35.5% improvement over baseline; F1-score: 0.76), high global MS symptom burden with an accuracy of 77.3% (51.3% improvement over baseline; F1-score: 0.77), severe fatigue with an accuracy of 73.8% (45.0% improvement over baseline; F1-score: 0.74), and poor sleep quality with an accuracy of 72.0% (28.1% improvement over baseline; F1-score: 0.70). Further, sensor data were largely sufficient for predicting symptom severity, while the prediction of depressive symptoms benefited from minimal active patient input in the form of response to two brief questions on the day before the prediction point.</p><p><strong>Conclusions: </strong>Our digital phenotyping approach using passive sensors on smartphones and fitness trackers may help patients with real-world, continuous, self-monitoring of common symptoms in their own environment and assist clinicians with better triage of patient needs for timely interventions in MS (and potentially other chronic neurological disorders).</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831633","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":"A genome-wide association study of anti-Müllerian hormone (AMH) levels in Samoan women.","authors":"Z Erdogan-Yildirim, J C Carlson, M Krishnan, J Z Zhang, G Lambert-Messerlian, T Naseri, S Viali, N L Hawley, S T McGarvey, D E Weeks, R L Minster","doi":"10.1101/2024.12.05.24318457","DOIUrl":"10.1101/2024.12.05.24318457","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;Can a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) help identify genetic variation or genes associated with circulating anti-Müllerian hormone (AMH) levels in Samoan women?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;We identified eleven genome-wide suggestive loci (strongest association signal in &lt;i&gt;ARID3A&lt;/i&gt; 19-946163-G-C [ &lt;i&gt;p&lt;/i&gt; = 2.32 × 10⁻⁷]) and seven transcriptome-wide significant genes ( &lt;i&gt;GINS2, SENP3, USP7, TUSC3, MAFA, METTL4, NDFIP1&lt;/i&gt; [all with a &lt;i&gt;p&lt;/i&gt; &lt; 2.50 × 10⁻⁶]) associated with circulating AMH levels in Samoan women.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already: &lt;/strong&gt;Three prior GWASs of AMH levels identified eight loci in premenopausal women of European ancestry &lt;i&gt;(AMH, MCM8, TEX41&lt;/i&gt; , &lt;i&gt;CHECK2, CDCA7&lt;/i&gt; , &lt;i&gt;EIF4EBP1, BMP4&lt;/i&gt; and an uncharacterized non-coding RNA gene &lt;i&gt;CTB-99A3.1&lt;/i&gt; ), among which the &lt;i&gt;MCM8&lt;/i&gt; locus was shared among all three studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design size duration: &lt;/strong&gt;We included a sample of 1,185 women from two independently recruited samples: a family study ( &lt;i&gt;n&lt;/i&gt; = 212; [age: 18 to 40 years]) recruited in 2002-03 from Samoa and American Samoa; and the Soifua Manuia Study ( &lt;i&gt;n&lt;/i&gt; = 973; age: 25 to 51 years), a crosssectional population-based study recruited in 2010 from Samoa.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials setting methods: &lt;/strong&gt;Serum AMH levels were measured using enzyme linked immunosorbent assays (ELISA). We performed GWASs in the two participant samples using a Cox mixed-effects model to account for AMH levels below detectable limits and adjusted for centered age, centered age², polity, and kinship via kinship matrix. The summary statistics were then meta-analyzed using a fixed-effect model. We annotated the variants with &lt;i&gt;p &lt;&lt;/i&gt; 1 × 10⁻⁵ and calculated posterior probability of causality for prioritization. We further annotated variants using FUMA and performed colocalization and transcriptome-wide association analysis. We also assessed whether any previously reported loci were replicated in our GWAS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main results and the role of chance: &lt;/strong&gt;We identified eleven novel genome-wide suggestive loci ( &lt;i&gt;p&lt;/i&gt; &lt; 1 × 10⁻⁵) associated with AMH levels and replicated &lt;i&gt;EIF4EBP1,&lt;/i&gt; a previously reported AMH locus, in the GWAS. The lead variant in &lt;i&gt;ARID3A&lt;/i&gt; , 19-946163-G-C is in high linkage disequilibrium ( &lt;i&gt;r&lt;/i&gt; ² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby &lt;i&gt;KISS1R&lt;/i&gt; is a biologically plausibility causal gene in the region; kisspeptin regulates ovarian follicle development and has been linked to AMH levels. Further investigation of the &lt;i&gt;ARID3A&lt;/i&gt; locus is warranted.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Limitations reasons for caution: &lt;/strong&gt;The main limitations of our study are the small sample size for a GWAS and the use of the transcription model trained on mostly European samples from the Genotype Tissue Expression (GTEx) project, which may have","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831568","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":"Strengthening evidence for text-based telehealth in post-operative care: A pragmatic study of the reach and effectiveness of two-way, text-based follow-up after voluntary medical male circumcision in South Africa.","authors":"Caryl Feldacker, Isabella Fabens, Tracy Dong, Khumbulani Moyo, Calsile Makhele, Motshana Phohole, Nelson Igaba, Sizwe Hlongwane, Jacqueline Pienaar, Maria Sardini, Felex Ndebele, Hannock Tweya, Marrianne Holec, Evelyn Waweru, Geoffrey Setswe","doi":"10.1101/2024.12.05.24317906","DOIUrl":"10.1101/2024.12.05.24317906","url":null,"abstract":"<p><p>Building upon evidence of safety and efficiency gains from a randomized control trial (RCT) in South Africa, we further scaled implementation of two-way, short message service (SMS), text-based (2wT) follow-up after voluntary medical male circumcision (VMMC). We aimed to determine if gains in adverse event (AE) identification and reduced follow-up visits could be maintained when 2wT was implemented in routine VMMC settings. A pragmatic, stepped wedge design (SWD) study was implemented across three districts in South Africa. Men ages 15 and older could opt into the 2wT telehealth follow-up approach when their facility was in the intervention period. Men in routine periods were offered the standard of care (SoC): in-person post-operative visits on days 2 and 7 as per national VMMC guidelines. 2wT participants were not required to attend any postoperative visits but could return for care if desired or referred. Two quality of care markers, safety (AE ascertainment rate) and efficiency (# in-person follow-up visits), were compared between groups. We aimed for at least 200 men per step to have 80% power to detect a change in AE rate from before to after 2wT was implemented. Secondary analysis explored response rates; client and site uptake; and AE details. Among 6842 clients in the intervention period, 2856 opted into 2wT (37.8%) across three intervention waves and two platforms (SMS or WhatsApp). Among those with post-operative follow-up, the AE ascertainment rate was higher among 2wT (0.60%) than SoC (0.13%) clients (p = 0.0018), demonstrating safety gains. On average, 2wT participants had 2.1 fewer visits compared to SoC clients (p<0.001), demonstrating gains in follow-up efficiency. Among 2wT men, 2069/2586 (80%) responded via 2wT over 14 days, demonstrating engagement in post-operative care. Of all intervention clients, 93 2wT (3.6%) and 342 (8.0%) SoC were considered lost to follow-up. In this expansion trial, we provided additional evidence that the 2wT approach maintains the quality of post-operative care for adult VMMC clients. 2wT should be scaled to augment in-person, post-operative visits after VMMC for eligible, interested males ages 15 and older. To achieve potential impact, effort is needed to improve access and uptake to 2wT among providers and sites, expanding the 2wT approach for other acute follow-up care especially among men.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831613","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":"Genetic Analysis of Psychosis Biotypes: Shared Ancestry-Adjusted Polygenic Risk and Unique Genomic Associations.","authors":"Cuihua Xia, Ney Alliey-Rodriguez, Carol A Tamminga, Matcheri S Keshavan, Godfrey D Pearlson, Sarah K Keedy, Brett Clementz, Jennifer E McDowell, David Parker, Rebekka Lencer, S Kristian Hill, Jeffrey R Bishop, Elena I Ivleva, Cindy Wen, Rujia Dai, Chao Chen, Chunyu Liu, Elliot S Gershon","doi":"10.1101/2024.12.05.24318404","DOIUrl":"10.1101/2024.12.05.24318404","url":null,"abstract":"<p><p>The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder and bipolar disorder with psychosis. Two recently developed <i>post hoc</i> ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes and isoforms showed significant genomic associations with specific Biotypes in Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in adult brain and fetal brain. TWAS inflation was addressed by inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes <i>TMEM140</i>, <i>ARTN</i>, <i>C1orf115</i>, <i>CYREN</i>, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831581","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}