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Polygenic Scores for Obstructive Sleep Apnoea Reveal Pathways Contributing to Cardiovascular Disease
No full textBackground: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors.
Methods: Using race/ethnic diverse samples from over 1.2 million individuals from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger\u27s MyCode, MGB Biobank, and the Human Phenotype Project, we developed and assessed PGSs for OSA, both without (BMIunadjOSA-PGS) and with adjustment for the genetic contributions of BMI (BMIadjOSA-PGS).
Findings: Adjusted odds ratios (ORs) for OSA per 1 standard deviation of the PGSs ranged from 1.38 to 2.75. The associations of BMIadjOSA- and BMIunadjOSA-PGSs with CVD outcomes in AoU shared both common and distinct patterns. Only BMIunadjOSA-PGS was associated with type 2 diabetes, heart failure, and coronary artery disease, while both BMIadjOSA- and BMIunadjOSA-PGSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA-PGS association with hypertension was driven by females (OR = 1.1, p-value = 0.002, OR = 1.01 p-value = 0.2 in males). OSA PGSs were also associated with body fat measures with some sex-specific associations.
Interpretation: Distinct components of OSA genetic risk are related and independent of obesity. Sex-specific associations with body fat distribution measures may explain differing OSA risks and associations with cardiometabolic morbidities between sexes.
Funding: R01AG080598
Predictors of Donor-Site Wound Complications Following Fibula Free Flap Reconstruction
No full textObjective: The fibula free flap (FFF) remains the workhorse flap for head and neck defects necessitating osteocutaneous reconstruction. Although lower extremity angiography, ultrasound (US), and other vascular studies are routinely used for fibula assessment and patient selection, predictors of donor-site morbidity following harvest remain poorly understood. We sought to investigate the factors associated with FFF donor-site complications.
Study design: Retrospective analysis of patients at a tertiary care center.
Setting: Tertiary care center.
Methods: In total, 119 patients undergoing FFF reconstruction during the years 2012 to 2022 were included. Multivariable logistic regression was used to identify independent predictors of soft-tissue donor-site wound complications.
Results: A total of 48 (40.3%) patients developed a donor-site wound complication with an average time to diagnosis of 24 days (±16) following surgery. In multivariable regression, history of alcohol use disorder (P = .0083) and method of donor-site closure (P = .0368) were independent predictors of donor-site wound complications. Split-thickness skin graft closure was associated with a 146% increased odds of wound complications (odds ratio [OR] = 2.46, 1.11-5.43, 95% confidence interval). Patient age, body mass index, Charlson comorbidity index, skin paddle size, and Doppler US characteristics were not predictive of postoperative donor-site morbidity.
Conclusion: Predictors of FFF donor-site wound complications included history of alcohol abuse and method of donor-site closure. This study highlights unique lower extremity Doppler US findings in patients undergoing FFF reconstruction in addition to modifiable risk factors associated with fibula donor-site morbidity and soft-tissue complications. Our findings underscore the need to critically evaluate wound closure techniques in this population
Clonal Dynamics and Somatic Evolution of Haematopoiesis in Mouse
No full textHaematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they independently self-renew in parallel over life, evenly contributing to differentiated progenitors and peripheral blood. The stem cell pool grows steadily over the mouse lifespan to about 70,000 cells, self-renewing about every 6 weeks. Aged mice did not display the profound loss of clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing showed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations, exhibiting a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse
Talking About Suffering in the Intensive Care Unit
No full textBackground: Some have hypothesized that talk about suffering can be used by clinicians to motivate difficult decisions, especially to argue for reducing treatment at the end of life. We examined how talk about suffering is related to decision-making for critically ill patients, by evaluating transcripts of conversations between clinicians and patients\u27 families.
Methods: We conducted a secondary qualitative content analysis of audio-recorded family meetings from a multicenter trial conducted in the adult intensive care units of five hospitals from 2012-2017 to look at how the term suffering and its variants were used. A coding guide was developed by consensus-oriented discussion by four members of the research team. Two coders independently evaluated each transcript. We followed an inductive approach to data analysis in reviewing transcripts; findings were iteratively discussed among study authors until consensus on key themes was reached.
Results: Of 146 available transcripts, 34 (23%) contained the word suffer or suffering at least once, with 58 distinct uses. Clinicians contributed 62% of first uses. Among uses describing the suffering of persons, 57% (n = 24) were related to a decision, but only 42% (n = 10) of decision-relevant uses accompanied a proposal to limit treatment, and only half of treatment-limiting uses (n = 5) were initiated by clinicians. The target terms had a variety of implicit meanings, including poor prognosis, reduced functioning, pain, discomfort, low quality of life, and emotional distress. Suffering was frequently attributed to persons who were unconscious.
Conclusions: Our results did not support the claim that the term suffering and its variants are used primarily by clinicians to justify limiting treatment, and the terms were not commonly used in our sample when decisions were requested. Still, when these terms were used, they were often used in a decision-relevant fashion
A Meta-Analysis of Diagnostic Yield and Clinical Utility of Genome and Exome Sequencing in Pediatric Rare and Undiagnosed Genetic Diseases
No full textPurpose: To systematically evaluate the diagnostic yield and clinical utility of genome sequencing (GS) and exome sequencing (ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases.
Methods: We conducted a meta-analysis of studies published between 2011 and 2023. To address study heterogeneity, comparative analyses included within-cohort studies using random-effects models.
Results: We identified 108 studies including 24,631 probands with diverse clinical indications. The pooled diagnostic yield among within-cohort studies (N = 13) for GWS was 34.2% (95% CI: 27.6-41.5; I2: 86%) vs 18.1% (95% CI: 13.1-24.6; I2: 89%) for non-GWS, with 2.4-times odds of diagnosis (95% CI: 1.40-4.04; P \u3c .05). The pooled diagnostic yield among within-cohort studies (N = 3) for GS was 30.6% (95% CI: 18.6-45.9; I2: 79%) vs 23.2% (95% CI: 18.5-28.7; I2: 58%) for ES, with 1.7-times the odds of diagnosis (95% CI: 0.94-2.92; P = .13). In first-line testing, the diagnostic yield tended to be higher for GS than for ES across clinical subgroups. The pooled clinical utility among patients with a positive diagnosis was 58.7% (95% CI: 47.3-69.2; I2: 81%) for GS and 54.5% (95% CI: 40.7-67.6; I2: 87%) for ES.
Conclusion: GS appears to have a higher diagnostic yield than ES, with similar clinical utility per positive diagnosis
FusionPub, a Therapeutic Landscape of Human Fusion Genes
Get PDFTo advance the development of fusion protein-targeting therapeutics, it is crucial to understand how patients with fusion oncoproteins have been treated and what small molecules have been studied. To fill this gap, we developed FusionPub, a knowledgebase of the therapeutic landscape of human fusion genes. We searched PubMed abstracts for 107K human fusion genes with 14K drugs. We also searched PubMed abstracts for 18K human fusion proteins, considering all gene synonyms of individual partner genes with 14K drugs. After manual curation, we found 17 342 records from 9623 PubMed abstracts. For these fusion genes and drugs, we provide a summary sentence of their relationship using the generative AI, details of the drugs, clinical trial records, common drug records from patient treatment history, etc. FusionPub will be a valuable and unique resource providing knowledge of the development of fusion gene targeting therapeutics
Evaluating Large Language Model Performance To Support the Diagnosis and Management of Patients With Primary Immune Disorders
No full textBackground: Generative artificial intelligence (GAI) is transforming health care in a variety of ways; however, the present utility of GAI for supporting clinicians who treat rare disease such as primary immune disorders (PIs) is not well studied. We evaluated the ability of 6 state-of-the-art large language models (LLMs) for providing clinical guidance about PIs.
Objective: To quantitatively and qualitatively measure the utility of current, open-source LLMs for diagnosing and providing helpful clinical decision support about PIs.
Methods: Five expert clinical immunologists each provided 5 real-world, anonymized PI case vignettes via multi-turn prompting to 6 LLMs (OpenAI GPT-4o, Llama-3.1-8B-Instruct, Llama-3.1-70B-Instruct, Mistral-7B-Instruct-v0.3, Mistral-Large-Instruct-2407, Mixtral-8x7B-Instruct-v0.1). We assessed the diagnostic accuracy of the LLMs and the quality of clinical reasoning using the Revised-IDEA (R-IDEA) score. Qualitative LLM assessment was made by immunologist narratives.
Results: Performance accuracy (\u3e88%) and R-IDEA scores (≥8) were superior for 3 models (GPT-4o, Llama-3.1-70B-Instruct, Mistral-Large-Instruct-2407), with GPT-4o achieving the highest diagnostic accuracy (96.2%). Conversely, the remaining 3 models fell below acceptable accuracy rates near 60% or lower and had poor R-IDEA scores (≤0.55), with Mistral-7B-Instruct-v0.3 attaining the worst diagnostic accuracy (42.3%). Compared with the 3 best-performing LLMs, the 3 worst-performing LLMs had a substantially lower median R-IDEA score (P \u3c .001). Interclass correlation coefficient for R-IDEA score assignments varied substantially by LLM, ranging from good to poor agreement, and did not appear to correlate with either diagnostic accuracy or median R-IDEA score. Qualitatively, immunologists identified several themes (eg, correctness, differential diagnosis appropriateness, relative conciseness of explanations) of relevance to PIs.
Conclusions: LLM can support diagnosis and management of PIs; however, further tuning is needed to optimize LLMs for best practice recommendations
A Multi-Level Gene-Diet Interaction Analysis of Fish Oil and 14 Polyunsaturated Fatty Acid Traits Identifies the FADS and GPR12 Loci
No full textFish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (p \u3c 5 × 10-8) in the FADS1-FADS2 gene cluster for total omega-3, omega-3%, docosapentaenoic acid (DHA), DHA%, and the omega-6 to omega-3 ratio. Among the interaction signals for omega-3%, the lead SNP, rs35473591 (C\u3eCT, CT allele frequency = 0.34), had a lower association effect size in the FOS-taking group (β = 0.35 for allele C) than that in the group without FOS (β = 0.42). Likewise, the effect sizes of associations between FOS and omega-3% varied across the three genotype groups (β = 0.45, 0.50, and 0.59, respectively, in C/C, C/CT, and CT/CT). Our gene-level aggregate and transcriptome-wide interaction analyses identified significant signals at two loci around FADS1-FADS2 and GPR12. The contribution of genome-wide gene-FOS interactions to phenotypic variance was statistically significant in omega-3-related traits. This systematic gene-FOS GWIS contributes to our understanding of the genetic architecture of circulating PUFAs underlying FOS response and informs personalized dietary recommendations
Investigation of a Pathogenic Inversion in UNC13D and Comprehensive Analysis of Chromosomal Inversions Across Diverse Datasets
No full textInversions are known contributors to the pathogenesis of genetic diseases. Identifying inversions poses significant challenges, making it one of the most demanding structural variants (SVs) to detect and interpret. Recent advancements in sequencing technologies and the development of publicly available SV datasets have substantially enhanced our capability to explore inversions. However, a cross-comparison in those datasets remains unexplored. In this study, we reported a proband with familial hemophagocytic lymphohistiocytosis type-3 carrying a splicing variant (c.1389+1G\u3eA) in trans with an inversion present in 0.006345% of individuals in gnomAD (v4.0) that disrupts UNC13D. Based on this result, we investigate the features of potentially pathogenic inversions in gnomAD which revealed 98.9% of them are rare and disrupt 5% of protein-coding genes associated with a phenotype in OMIM. We then conducted a comparative analysis of additional public datasets, including DGV, 1KGP, and two recent studies from the Human Genome Structural Variation Consortium which revealed common and dataset-specific inversion characteristics suggesting methodology detection biases. Next, we investigated the genetic features of inversions disrupting the protein-coding genes. Notably, we found that the majority of protein-coding genes in OMIM disrupted by inversions are associated with autosomal recessive phenotypes supporting the hypothesis that inversions in trans with other variants are potential hidden causes of monogenic diseases. This effort aims to fill the gap in our understanding of the molecular characteristics of inversions with low frequency in the population and highlight the importance of identifying them in rare disease studies
Understanding Dental Hygienists’ Knowledge, Attitudes, and Practices Regarding HPV Vaccination
No full textThe American Dental Association and American Academy of Pediatric Dentistry encourage oral health professionals to strongly recommend human papillomavirus (HPV) vaccination to prevent HPV-associated oropharyngeal cancer. This study examined oral health professionals\u27 knowledge, attitudes, and practices regarding HPV vaccination. We used purposive sampling to recruit participants through state and national oral health societies and social media platforms. Flyers outlining eligibility criteria were distributed, and eligible participants completed an online survey. Primary measures included participants\u27 HPV-related knowledge, attitudes, and practices, and willingness to receive HPV-related training and recommend HPV vaccination to patients, including parents of adolescents. Only responses from dental hygienists (n = 380) were analyzed due to an insufficient sample size of dentists. Mostly female, White, and practicing in urban areas, hygienists had overall low awareness of the high prevalence of HPV and HPV vaccine efficacy in preventing several types of HPV-associated cancers. While the discussion of the HPV-oropharyngeal cancer link was perceived as relevant to their practice, participants generally disagreed with administering the vaccine in the dental office. Less than half of participants believed they were responsible for recommending the vaccine with low perceived knowledge and self-efficacy to discuss HPV vaccination with parents of adolescents. Despite the current lack of HPV vaccine recommendations in their practice, more than half of the participants were willing to educate their patients about the importance of the vaccine to prevent oropharyngeal cancer. HPV-focused educational interventions tailored to oral health practice may improve dental hygienists\u27 confidence and motivation to promote HPV vaccination for oral cancer prevention