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In this reply, we address a comment on our paper “Combining probability with qualitative degree-of-certainty metrics in assessment” (Helgeson et al. Clim Change 149(3):517–525, 2018). Our original paper proposes an incremental systematization of confidence and likelihood language used by the Intergovernmental Panel on Climate Change (IPCC). Our goals were to improve consistency across findings and support use of confidence judgments in decision making. The comment critiques our proposal and recommends against its adoption. We argue that this recommendation is based on two misunderstandings. The first concerns trading off confidence against the precision of a finding (our proposal endorses and systematizes the practice). We defend this practice and attribute opposition to an overzealous Bayesianism inapt for the IPCC context. The second misunderstanding concerns our purported commitment to a specific procedure for producing confidence judgements. We clarify that our proposal makes no such commitment. We also note, contrary to the comment’s claim, that a version of the procedure in question has been used in the IPCC’s Sixth Assessment Report. 

Abstract Mendelian Randomization (MR) studies are threatened by population stratification, batch effects, and horizontal pleiotropy. Although a variety of methods have been proposed to mitigate those problems, residual biases may still remain, leading to highly statistically significant false positives in large databases. Here we describe a suite of sensitivity analysis tools that enables investigators to quantify the robustness of their findings against such validity threats. Specifically, we propose the routine reporting of sensitivity statistics that reveal the minimal strength of violations necessary to explain away the MR results. We further provide intuitive displays of the robustness of the MR estimate to any degree of violation, and formal bounds on the worst-case bias caused by violations multiple times stronger than observed variables. We demonstrate how these tools can aid researchers in distinguishing robust from fragile findings by examining the effect of body mass index on diastolic blood pressure and Townsend deprivation index. 

Abstract Inference of clinical phenotypes is a fundamental task in precision medicine, and has therefore been heavily investigated in recent years in the context of electronic health records (EHR) using a large arsenal of machine learning techniques, as well as in the context of genetics using polygenic risk scores (PRS). In this work, we considered the epigenetic analog of PRS, methylation risk scores (MRS), a linear combination of methylation states. We measured methylation across a large cohort ( n  = 831) of diverse samples in the UCLA Health biobank, for which both genetic and complete EHR data are available. We constructed MRS for 607 phenotypes spanning diagnoses, clinical lab tests, and medication prescriptions. When added to a baseline set of predictive features, MRS significantly improved the imputation of 139 outcomes, whereas the PRS improved only 22 (median improvement for methylation 10.74%, 141.52%, and 15.46% in medications, labs, and diagnosis codes, respectively, whereas genotypes only improved the labs at a median increase of 18.42%). We added significant MRS to state-of-the-art EHR imputation methods that leverage the entire set of medical records, and found that including MRS as a medical feature in the algorithm significantly improves EHR imputation in 37% of lab tests examined (median R 2 increase 47.6%). Finally, we replicated several MRS in multiple external studies of methylation (minimum p -value of 2.72 × 10 −7 ) and replicated 22 of 30 tested MRS internally in two separate cohorts of different ethnicity. Our publicly available results and weights show promise for methylation risk scores as clinical and scientific tools. 

Abstract Background Large medical centers in urban areas, like Los Angeles, care for a diverse patient population and offer the potential to study the interplay between genetic ancestry and social determinants of health. Here, we explore the implications of genetic ancestry within the University of California, Los Angeles (UCLA) ATLAS Community Health Initiative—an ancestrally diverse biobank of genomic data linked with de-identified electronic health records (EHRs) of UCLA Health patients ( N =36,736). Methods We quantify the extensive continental and subcontinental genetic diversity within the ATLAS data through principal component analysis, identity-by-descent, and genetic admixture. We assess the relationship between genetically inferred ancestry (GIA) and >1500 EHR-derived phenotypes (phecodes). Finally, we demonstrate the utility of genetic data linked with EHR to perform ancestry-specific and multi-ancestry genome and phenome-wide scans across a broad set of disease phenotypes. Results We identify 5 continental-scale GIA clusters including European American (EA), African American (AA), Hispanic Latino American (HL), South Asian American (SAA) and East Asian American (EAA) individuals and 7 subcontinental GIA clusters within the EAA GIA corresponding to Chinese American, Vietnamese American, and Japanese American individuals. Although we broadly find that self-identified race/ethnicity (SIRE) is highly correlated with GIA, we still observe marked differences between the two, emphasizing that the populations defined by these two criteria are not analogous. We find a total of 259 significant associations between continental GIA and phecodes even after accounting for individuals’ SIRE, demonstrating that for some phenotypes, GIA provides information not already captured by SIRE. GWAS identifies significant associations for liver disease in the 22q13.31 locus across the HL and EAA GIA groups (HL p -value=2.32×10 −16 , EAA p -value=6.73×10 −11 ). A subsequent PheWAS at the top SNP reveals significant associations with neurologic and neoplastic phenotypes specifically within the HL GIA group. Conclusions Overall, our results explore the interplay between SIRE and GIA within a disease context and underscore the utility of studying the genomes of diverse individuals through biobank-scale genotyping linked with EHR-based phenotyping. 

Abstract One of the core challenges in applying machine learning and artificial intelligence to medicine is the limited availability of annotated medical data. Unlike in other applications of machine learning, where an abundance of labeled data is available, the labeling and annotation of medical data and images require a major effort of manual work by expert clinicians who do not have the time to annotate manually. In this work, we propose a new deep learning technique (SLIVER-net), to predict clinical features from 3-dimensional volumes using a limited number of manually annotated examples. SLIVER-net is based on transfer learning, where we borrow information about the structure and parameters of the network from publicly available large datasets. Since public volume data are scarce, we use 2D images and account for the 3-dimensional structure using a novel deep learning method which tiles the volume scans, and then adds layers that leverage the 3D structure. In order to illustrate its utility, we apply SLIVER-net to predict risk factors for progression of age-related macular degeneration (AMD), a leading cause of blindness, from optical coherence tomography (OCT) volumes acquired from multiple sites. SLIVER-net successfully predicts these factors despite being trained with a relatively small number of annotated volumes (hundreds) and only dozens of positive training examples. Our empirical evaluation demonstrates that SLIVER-net significantly outperforms standard state-of-the-art deep learning techniques used for medical volumes, and its performance is generalizable as it was validated on an external testing set. In a direct comparison with a clinician panel, we find that SLIVER-net also outperforms junior specialists, and identifies AMD progression risk factors similarly to expert retina specialists.