Clinical prioritization of reported disease variants in asymptomatic individuals

无症状个体中报告的疾病变异的临床优先顺序

• 批准号: 9309017
• 负责人: Christopher Cassa
• 金额: $ 24.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309017
• 关键词: Address; Affect; Algorithms; Ambulatory Care; Bayesian Method; Behavioral; Benign; Caring; Case Study; Classification; Clinical; Clinical Trials; Cohort Studies; Confidence Intervals; Dangerousness; Data; Data Set; Databases; Development; Diagnostic; Disease; Environmental Risk Factor; Epidemiology; Exclusion; Foundations; Frequencies; Future; Gene Frequency; Genetic Risk; Genetic Variation; Genome; Gold; Hereditary Disease; Hypertrophic Cardiomyopathy; Incidence; Individual; Laboratories; Link; Literature; Measures; Medical; Medical Genetics; Mendelian disorder; Methodology; Methods; Minor; Morbidity - disease rate; Neurofibromatoses; Online Mendelian Inheritance In Man; Pathogenicity; Patient Care; Patients; Penetrance; Pharmaceutical Preparations; Physicians; Population; Population Genetics; Positioning Attribute; Prevalence; Primary Health Care; Probability; Process; Publications; Publishing; Rare Diseases; Reporting; Research; Risk; Risk Estimate; Source; Standardization; Structure; Sum; Surveys; Symptoms; Tail; Translating; Variant; base; burden of illness; case control; clinical application; clinical practice; clinical risk; clinically relevant; clinically significant; cohort; cost; disorder risk; epidemiologic data; genetic variant; genome sequencing; genome-wide; genomic data; genomic variation; improved; individual patient; novel; novel strategies; population based; public health relevance; research clinical testing; response; risk variant; whole genome

DESCRIPTION (provided by applicant): Whole genome sequencing (WGS) has the potential to improve medical care, but much effort remains to translate sequence data into meaningful clinical interpretations. WGS interpretation must address both newly observed genetic variants that are likely to be harmful, as well as the review of over 150,000 variants that are already reported to be associated with disease from the medical and scientific literature. Many of these discoveries were made in small cohort and case studies, making it difficult to translate these into disease risks for asymptomatic individuals that carry these variants. Without accurate risk estimates for these associations, we may potentially expose healthy patients to false positive findings, leading to needless diagnostic workups and screenings that will substantially increase medical costs and patient morbidity. Central to WGS interpretation is the development of a standardized methodology to filter likely benign results, and to prioritize those variants that may be clinically significant and scientifically valid. While many of these previously identified variats are associated with Mendelian disorders that are individually rare, (e.g. hypertrophic cardiomyopathy and neurofibromatosis,) these disorders are collectively common, forming a long tail that confers disease risk for many individuals. Because each of these diseases is so rare, it is hard to envision a specialized interpretive approach to calculate risk for each disease so we propose a systematic approach that is broadly applicable across many rare diseases to assess variant disease risk. To meet this urgent need, we will develop a novel approach that estimates the penetrance of disease- associated variants using the prior probability of each disease, and the population frequencies of all of the known genetic variants for that disease for affected and unaffected individuals. This prior probability of disease is measured as the prevalence, or the proportion of individuals in a population affected with a disorder. Because the prevalence of a Mendelian disease is actually a combination of the penetrance and frequency of all of its genetic variation (as well as other behavioral and environmental factors) we propose to estimate these penetrance values using the disease prevalence and distribution of associated variation, for each disease. If there is only one variant associated with a disease, the total penetrance and population frequency for that disease should be closely correlated with disease prevalence, but if there are many disease-associated variants, each contributes less to the overall burden of diseases, adjusted by its frequency in the population. We will then use these penetrance estimates to establish genome-wide filtering cutoffs for likely benign variation and to prioritize observed WGS variation for review by clinical geneticists. We then propose to use these values to filter and rank the observed variation in individual WGS datasets in an existing clinical trial, and to compare these with existing clinical genetics interpretations.

描述（由申请人提供）：整个基因组测序（WGS）具有改善医疗服务的潜力，但是将序列数据转化为有意义的临床解释仍有很多努力。 WGS的解释必须解决可能有害有害的新观察到的遗传变异，以及对已经据报道与医学和科学文献中疾病有关的150,000多种变体的审查。这些发现中的许多是在小型队列和案例研究中进行的，因此很难将其翻译成 携带这些变体的无症状个体的疾病风险。如果没有对这些关联进行准确的风险估计，我们可能会使健康的患者有假阳性发现，从而导致不必要的诊断检查和筛查，从而大大增加医疗费用和患者的发病率。 WGS解释的核心是开发标准化方法，以过滤可能的良性结果，并优先考虑那些可能的变体 在临床上具有重要意义，并且科学有效。尽管这些先前鉴定的变体中有许多与孟德尔疾病相关，这些疾病是罕见的（例如肥厚的心肌病和神经纤维瘤病），但这些疾病统一是普遍的，形成了长长的尾巴，赋予许多人的疾病风险。由于这些疾病中的每一种都是如此罕见，因此很难设想一种专门的解释方法来计算每种疾病的风险，因此我们提出了一种系统的方法，该方法广泛适用于许多罕见疾病以评估变异疾病风险。 为了满足这种迫切的需求，我们将开发一种新颖的方法，该方法使用每种疾病的先前概率估算疾病相关变体的外观，以及该疾病的所有已知遗传变异的种群频率对受影响和未受影响的个体而言。这种先前的疾病概率被衡量为受疾病影响的人群中的个体的患病率或比例。因为孟德尔疾病的流行实际上是其所有遗传变异（以及其他行为和环境因素）的外观和频率的结合，所以我们建议使用相关变异的疾病流行和分布来估算这些渗透率，以估算这些渗透率。每种疾病。如果只有一种与疾病相关的变体，则该疾病的总渗透率和人口频率应与疾病患病率密切相关，但是如果有许多与疾病相关的变体，则每种变体对疾病的整体负担造成的贡献较小，受到调整的调整。它在人口中的频率。然后，我们将使用这些渗透率估计值来建立全基因组滤波截止，以实现良性变化，并优先考虑观察到的WGS变异，以供临床遗传学家进行审查。然后，我们建议使用这些值在现有的临床试验中过滤和排除单个WGS数据集的观察到的变化，并将其与现有的临床遗传学解释进行比较。