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To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.
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Comunicación Celular/fisiología , ARN/metabolismo , Adulto , Líquidos Corporales/química , Ácidos Nucleicos Libres de Células/metabolismo , MicroARN Circulante/metabolismo , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN/métodos , Programas InformáticosRESUMEN
BACKGROUND: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified. METHODS: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks. RESULTS: Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011. CONCLUSIONS: The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.).
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Pruebas de Función Respiratoria , Insuficiencia Respiratoria , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/economía , Enfermedades Pulmonares/etnología , Enfermedades Pulmonares/terapia , Trasplante de Pulmón/estadística & datos numéricos , Encuestas Nutricionales/estadística & datos numéricos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/economía , Enfermedad Pulmonar Obstructiva Crónica/etnología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Grupos Raciales , Pruebas de Función Respiratoria/clasificación , Pruebas de Función Respiratoria/economía , Pruebas de Función Respiratoria/normas , Espirometría , Estados Unidos/epidemiología , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/economía , Insuficiencia Respiratoria/etnología , Insuficiencia Respiratoria/terapia , Negro o Afroamericano/estadística & datos numéricos , Blanco/estadística & datos numéricos , Evaluación de la Discapacidad , Ayuda a Lisiados de Guerra/clasificación , Ayuda a Lisiados de Guerra/economía , Ayuda a Lisiados de Guerra/estadística & datos numéricos , Personas con Discapacidad/clasificación , Personas con Discapacidad/estadística & datos numéricos , Enfermedades Profesionales/diagnóstico , Enfermedades Profesionales/economía , Enfermedades Profesionales/etnología , Financiación Gubernamental/economía , Financiación Gubernamental/estadística & datos numéricosRESUMEN
BACKGROUND: The National Kidney Foundation and American Society of Nephrology Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease recently recommended a new race-free creatinine-based equation for eGFR. The effect on recommended clinical care across race and ethnicity groups is unknown. METHODS: We analyzed nationally representative cross-sectional questionnaires and medical examinations from 44,360 participants collected between 2001 and 2018 by the National Health and Nutrition Examination Survey. We quantified the number and proportion of Black, White, Hispanic, and Asian/Other adults with guideline-recommended changes in care. RESULTS: The new equation, if applied nationally, could assign new CKD diagnoses to 434,000 (95% confidence interval [CI], 350,000 to 517,000) Black adults, reclassify 584,000 (95% CI, 508,000 to 667,000) to more advanced stages of CKD, restrict kidney donation eligibility for 246,000 (95% CI, 189,000 to 303,000), expand nephrologist referrals for 41,800 (95% CI, 19,800 to 63,800), and reduce medication dosing for 222,000 (95% CI, 169,000 to 275,000). Among non-Black adults, these changes may undo CKD diagnoses for 5.51 million (95% CI, 4.86 million to 6.16 million), reclassify 4.59 million (95% CI, 4.28 million to 4.92 million) to less advanced stages of CKD, expand kidney donation eligibility for 3.96 million (95% CI, 3.46 million to 4.46 million), reverse nephrologist referral for 75,800 (95% CI, 35,400 to 116,000), and reverse medication dose reductions for 1.47 million (95% CI, 1.22 million to 1.73 million). The racial and ethnic mix of the populations used to develop eGFR equations has a substantial effect on potential care changes. CONCLUSION: The newly recommended 2021 CKD-EPI creatinine-based eGFR equation may result in substantial changes to recommended care for US patients of all racial and ethnic groups.
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Insuficiencia Renal Crónica , Adulto , Humanos , Creatinina , Tasa de Filtración Glomerular , Encuestas Nutricionales , Estudios Transversales , Insuficiencia Renal Crónica/diagnósticoRESUMEN
Importance: Since 2013, the American College of Cardiology (ACC) and American Heart Association (AHA) have recommended the pooled cohort equations (PCEs) for estimating the 10-year risk of atherosclerotic cardiovascular disease (ASCVD). An AHA scientific advisory group recently developed the Predicting Risk of cardiovascular disease EVENTs (PREVENT) equations, which incorporated kidney measures, removed race as an input, and improved calibration in contemporary populations. PREVENT is known to produce ASCVD risk predictions that are lower than those produced by the PCEs, but the potential clinical implications have not been quantified. Objective: To estimate the number of US adults who would experience changes in risk categorization, treatment eligibility, or clinical outcomes when applying PREVENT equations to existing ACC and AHA guidelines. Design, Setting, and Participants: Nationally representative cross-sectional sample of 7765 US adults aged 30 to 79 years who participated in the National Health and Nutrition Examination Surveys of 2011 to March 2020, which had response rates ranging from 47% to 70%. Main Outcomes and Measures: Differences in predicted 10-year ASCVD risk, ACC and AHA risk categorization, eligibility for statin or antihypertensive therapy, and projected occurrences of myocardial infarction or stroke. Results: In a nationally representative sample of 7765 US adults aged 30 to 79 years (median age, 53 years; 51.3% women), it was estimated that using PREVENT equations would reclassify approximately half of US adults to lower ACC and AHA risk categories (53.0% [95% CI, 51.2%-54.8%]) and very few US adults to higher risk categories (0.41% [95% CI, 0.25%-0.62%]). The number of US adults receiving or recommended for preventive treatment would decrease by an estimated 14.3 million (95% CI, 12.6 million-15.9 million) for statin therapy and 2.62 million (95% CI, 2.02 million-3.21 million) for antihypertensive therapy. The study estimated that, over 10 years, these decreases in treatment eligibility could result in 107â¯000 additional occurrences of myocardial infarction or stroke. Eligibility changes would affect twice as many men as women and a greater proportion of Black adults than White adults. Conclusion and Relevance: By assigning lower ASCVD risk predictions, application of the PREVENT equations to existing treatment thresholds could reduce eligibility for statin and antihypertensive therapy among 15.8 million US adults.
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While tens of thousands of pathogenic variants are used to inform the many clinical applications of genomics, there remains limited information on quantitative disease risk for the majority of variants used in clinical practice. At the same time, rising demand for genetic counselling has prompted a growing need for computational approaches that can help interpret genetic variation. Such tasks include predicting variant pathogenicity and identifying variants that are too common to be penetrant. To address these challenges, researchers are increasingly turning to integrative informatics approaches. These approaches often leverage vast sources of data, including electronic health records and population-level allele frequency databases (e.g. gnomAD), as well as machine learning techniques such as support vector machines and deep learning. In this review, we highlight recent informatics and machine learning approaches that are improving our understanding of pathogenic variation and discuss obstacles that may limit their emerging role in clinical genomics.
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Biología Computacional/tendencias , Genoma Humano/genética , Genómica/tendencias , Aprendizaje Automático/tendencias , Bases de Datos Genéticas , HumanosAsunto(s)
Tasa de Filtración Glomerular , Factores Raciales , Insuficiencia Renal Crónica/clasificación , Insuficiencia Renal Crónica/fisiopatología , Población Negra , Creatinina/sangre , Cistatina C/sangre , Humanos , Conceptos Matemáticos , Insuficiencia Renal Crónica/etnología , Población BlancaAsunto(s)
Negro o Afroamericano , Creatinina/sangre , Tasa de Filtración Glomerular , Riñón/fisiopatología , Grupos Raciales , Insuficiencia Renal Crónica/diagnóstico , Adulto , Algoritmos , Femenino , Humanos , Masculino , Encuestas Nutricionales , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We hypothesize that considering other socioeconomic and environmental factors can better predict and stratify the risk of COPD in both non-smokers and smokers. We performed longitudinal analysis of COPD in the UK Biobank to develop the Socioeconomic and Environmental Risk Score (SERS) which captures additive and cumulative environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. We tested the ability of SERS to predict and stratify the risk of COPD in current, previous, and never smokers of European and non-European ancestries in comparison to a composite genome-wide polygenic risk score (PGS). We tested associations using Cox regression models and assessed the predictive performance of models using Harrell's C index. SERS (C index = 0.770, 95% CI 0.756 to 0.784) was more predictive of COPD than smoking status (C index = 0.738, 95% CI 0.724 to 0.752), pack-years (C index = 0.742, 95% CI 0.727 to 0.756). Compared to the remaining population, individuals in the highest decile of the SERS had hazard ratios (HR) = 7.24 (95% CI 6.51 to 8.05, P < 0.0001) for incident COPD. Never smokers in the highest decile of exposure risk were more likely to develop COPD than previous and current smokers in the lowest decile with HR=4.95 (95% CI 1.56 to 15.69, P=6.65×10-3) and 2.92 (95%CI 1.51 to 5.61, P=1.38×10-3), respectively. In general, the prediction accuracy of SERS was lower in the non-European populations compared to the European evaluation set. In addition to genetic factors, socioeconomic and environmental factors beyond smoking can predict and stratify COPD risk for both non- and smoking individuals. Smoking status is often considered in screening; other non-smoking environmental and non-genetic variables should be evaluated prospectively for their clinical utility.
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Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We perform a longitudinal analysis of COPD in the UK Biobank to derive and validate the Socioeconomic and Environmental Risk Score which captures additive and cumulative environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. The Socioeconomic and Environmental Risk Score is more predictive of COPD than smoking status and pack-years. Individuals in the highest decile of the risk score have a greater risk for incident COPD compared to the remaining population. Never smokers in the highest decile of exposure risk are more likely to develop COPD than previous and current smokers in the lowest decile. In general, the prediction accuracy of the Social and Environmental Risk Score is lower in non-European populations. While smoking status is often considered in screening COPD, our finding highlights the importance of other non-smoking environmental and socioeconomic variables.
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Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Factores de Riesgo , Fumar/efectos adversos , Fumar/epidemiologíaRESUMEN
Innovations in robotics, virtual and augmented reality, and artificial intelligence are being rapidly adopted as tools of "digital surgery". Despite its quickly emerging role, digital surgery is not well understood. A recent study defines the term itself, and then specifies ethical issues specific to the field. These include privacy and public trust, consent, and litigation.
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With the increasing number of FDA-approved artificial intelligence (AI) systems, the financing of these technologies has become a primary gatekeeper to mass clinical adoption. Reimbursement models adapted for current payment schemes, including per-use rates, are feasible for early AI products. Alternative and complementary models may offer future payment options for value-based AI. A successful reimbursement strategy will align interests across stakeholders to guide value-based and cost-effective improvements to care.
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Parkinson's disease (PD) lacks sensitive, objective, and reliable measures for disease progression and response. This presents a challenge for clinical trials given the multifaceted and fluctuating nature of PD symptoms. Innovations in digital health and wearable sensors promise to more precisely measure aspects of patient function and well-being. Beyond research trials, digital biomarkers and clinical outcome assessments may someday support clinician-initiated or closed-loop treatment adjustments. A recent study from Verily Life Sciences presents results for a smartwatch-based motor exam intended to accelerate the development and evaluation of therapies for PD.
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Nearly half of US adults have hypertension, and three in four cases are not well-controlled. Due to structural barriers, underserved communities face greater burdens of disease, less consistent management, and worse outcomes. Mobile technology presents an opportunity to reduce financial, geographic, and workforce barriers, but little data currently support its use in populations with digital disparities. A recent article by Khoong et al. systematically reviews the literature to quantify outcomes for these populations and provide a roadmap toward more inclusive mobile health strategies.
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Advances in medical machine learning are expected to help personalize care, improve outcomes, and reduce wasteful spending. In quantifying potential benefits, it is important to account for constraints arising from clinical workflows. Practice variation is known to influence the accuracy and generalizability of predictive models, but its effects on cost-effectiveness and utilization are less well-described. A simulation-based approach by Misic and colleagues goes beyond simple performance metrics to evaluate how process variables may influence the impact and financial feasibility of clinical prediction algorithms.
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Computational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction. Still, lack of interpretability remains a significant barrier to clinical integration. We present an approach for predicting clinically-relevant molecular phenotypes from whole-slide histopathology images using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5700 samples to train deep learning models for cell and tissue classification that can exhaustively map whole-slide images at two and four micron-resolution. Cell- and tissue-type model outputs are combined into 607 HIFs that quantify specific and biologically-relevant characteristics across five cancer types. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment and can predict diverse molecular signatures (AUROC 0.601-0.864), including expression of four immune checkpoint proteins and homologous recombination deficiency, with performance comparable to 'black-box' methods. Our HIF-based approach provides a comprehensive, quantitative, and interpretable window into the composition and spatial architecture of the tumor microenvironment.