Platform to support clinical variant interpretation through probabilistic assessment of functional evidence

类似SBIR第一阶段赠款的项目摘要 现在只需数百美元就可以对整个患者基因组进行测序，而且价格仍在下降。医生 现在常规地订购大型基因组作为诊断疾病和指导治疗的一种方式。而 这些测试的广泛使用有利于患者护理，但也带来了大规模数据的挑战 解释。目前，基因检测发现的大多数独特变异都没有足够的证据证明 分类.这些“意义不明的变异体”（VUS）阻碍了致命性结核病的及时诊断和治疗。 例如心脏病和癌症。需要采取更好的积极主动的办法， 被归类为VUS的变体数量。 在实验室中进行的功能测定是用于基因分类的重要证据来源 变体。从历史上看，这些实验一直是低通量的，一次生成一个变体的数据。 此外，这样的实验是反应性的，这意味着它们仅在给定的变体已经 在诊所观察。为了积极扩展遗传变异特征，一些学术实验室 最近开发了变异效应的多重测定（MAVE），它收集了数千个 蛋白质变体在一个实验中。MAVE作为一种高通量功能性的生物技术的来源具有很大的前景。 证据尽管如此，目前还没有商业平台来策划和强大地分析大型 学术实验室生成越来越多的MAVE数据集， 解释。因此，这些数据为拯救生命的医疗决策提供信息的潜力尚未实现。 为了满足改善临床变异解释的需求，Constantiam Biosciences正在开发VarifyTM， 首个专门将MAVE数据转换为可操作信息的平台， 临床变异解释。Varify为基因组解释领域带来了两项关键创新： 贝叶斯推理的应用，这是处理不确定性的最佳证明方法， 编程，一种新的计算技术，允许统计推断有效地执行 准确反映数据生成条件的模型。支持第一阶段 Constantiam Biosciences开发了Varify的早期原型。公司将建设 在这些初步努力的基础上，执行第一阶段的SBIR计划，目标是开发和评估 Varify的变体效应推理框架。目标1的重点是增强现有的早期变异效应 推理框架包括对MAVE中存在的信号破坏过程的影响进行建模的模块 可能扭曲和掩盖变异效应的实验。将不断评价扩大的框架 使用模拟数据（目标1）并应用于BRCA 1和PTEN的现有MAVE数据集（目标2）。成功 这些目标的完成将为Varify的扩展框架提供关键的概念验证，并支持 第二阶段计划，将更广泛地应用Varify，并开发商业化产品。

PROJECT SUMMARY FOR PREDICATE SBIR PHASE I GRANT Entire patient genomes can now be sequenced for hundreds of dollars, and the price is still falling. Physicians now routinely order large gene panels as a way of diagnosing disease and guiding treatment. While the widespread use of these tests is beneficial for patient care, it also introduces a challenge of large-scale data interpretation. Currently, most unique variants uncovered by genetic tests have insufficient evidence for confident classification. These “variants of unknown significance” (VUS) hinder timely diagnosis and treatment of deadly diseases such as heart disease and cancer. An improved and proactive approach is needed to decrease the number of variants that are classified as VUS. Functional assays performed in laboratories are important sources of evidence used for classification of gene variants. Historically, these experiments have been low-throughput, generating data for one variant at a time. Furthermore, such experiments are reactive, meaning they are performed only after a given variant has been observed in the clinic. To proactively expand genetic variant characterization, several academic laboratories have recently developed Multiplexed Assays of Variant Effect (MAVEs), which collect data on thousands of protein variants in a single experiment. MAVEs hold great promise as a source of high-throughput functional evidence. Nonetheless, there are currently no commercial platforms that curate and robustly analyze the large and growing number of MAVE datasets being generated by academic labs to inform clinical variant interpretations. As a result, the potential for these data to inform lifesaving medical decisions is unrealized. To address the need for improved clinical variant interpretation, Constantiam Biosciences is developing VarifyTM, a first of its kind platform specializing in the translation of MAVE data into actionable information to support clinical variant interpretation. Varify brings two key innovations to the field of genomic interpretation: the application of Bayesian inference, which is the best proven method for handling uncertainty, and probabilistic programming, a novel computational technique that allows statistical inference to be performed efficiently on models that accurately reflect the conditions under which the data were generated. To support the Phase I program, Constantiam Biosciences has developed an early-stage prototype of Varify. The company will build upon these preliminary efforts to execute the Phase I SBIR program with the goal of developing and assessing Varify’s variant effect inference framework. Aim 1 is focused on augmenting the existing early-stage variant effect inference framework to include modules that model the influence of signal-corrupting processes present in MAVE experiments that can distort and obscure variant effects. The expanded framework will be continuously evaluated using simulated data (Aim 1) and applied on existing MAVE data sets for BRCA1 and PTEN (Aim 2). Successful completion of these aims will provide critical proof-of-concept for Varify’s expanded framework and support a Phase II program that will apply Varify more broadly and develop a commercial-ready product.