Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria.

Recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) for interpreting sequence variants specify the use of computational predictors as "supporting" level of evidence for pathogenicity or benignity using criteria PP3 and BP4, respectively. However, score intervals defined by tool developers, and ACMG/AMP recommendations that require the consensus of multiple predictors, lack quantitative support. Previously, we described a probabilistic framework that quantified the strengths of evidence (supporting, moderate, strong, very strong) within ACMG/AMP recommendations. We have extended this framework to computational predictors and introduce a new standard that converts a tool's scores to PP3 and BP4 evidence strengths. Our approach is based on estimating the local positive predictive value and can calibrate any computational tool or other continuous-scale evidence on any variant type. We estimate thresholds (score intervals) corresponding to each strength of evidence for pathogenicity and benignity for thirteen missense variant interpretation tools, using carefully assembled independent data sets. Most tools achieved supporting evidence level for both pathogenic and benign classification using newly established thresholds. Multiple tools reached score thresholds justifying moderate and several reached strong evidence levels. One tool reached very strong evidence level for benign classification on some variants. Based on these findings, we provide recommendations for evidence-based revisions of the PP3 and BP4 ACMG/AMP criteria using individual tools and future assessment of computational methods for clinical interpretation.

Proteomic Analysis of Huntington's Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets.

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters the function of the HTT protein. Although HTT is expressed in different tissues, the medium-spiny projection neurons (MSNs) in the striatum are particularly vulnerable in HD. Thus, we sought to define the proteome of human HD patient-derived MSNs. We differentiated HD72-induced pluripotent stem cells and isogenic controls into MSNs and carried out quantitative proteomic analysis. Using data-dependent acquisitions with FAIMS for label-free quantification on the Orbitrap Lumos mass spectrometer, we identified 6323 proteins with at least two unique peptides. Of these, 901 proteins were altered significantly more in the HD72-MSNs than in isogenic controls. Functional enrichment analysis of upregulated proteins demonstrated extracellular matrix and DNA signaling (DNA replication pathway, double-strand break repair, G1/S transition) with the highest significance. Conversely, processes associated with the downregulated proteins included neurogenesis-axogenesis, the brain-derived neurotrophic factor-signaling pathway, Ephrin-A:EphA pathway, regulation of synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-γ signaling, immune system major histocompatibility complex, lipid metabolism, and cellular response to stimulus. Moreover, proteins involved in the formation and maintenance of axons, dendrites, and synapses (e.g., septin protein members) were dysregulated in HD72-MSNs. Importantly, lipid metabolism pathways were altered, and using quantitative image analysis, we found that lipid droplets accumulated in the HD72-MSN, suggesting a deficit in the turnover of lipids possibly through lipophagy. Our proteomics analysis of HD72-MSNs identified relevant pathways that are altered in MSNs and confirm current and new therapeutic targets for HD.

Evaluating construct validity of computable acute respiratory distress syndrome definitions in adults hospitalized with COVID-19: an electronic health records based approach.

BACKGROUND: Evolving ARDS epidemiology and management during COVID-19 have prompted calls to reexamine the construct validity of Berlin criteria, which have been rarely evaluated in real-world data. We developed a Berlin ARDS definition (EHR-Berlin) computable in electronic health records (EHR) to (1) assess its construct validity, and (2) assess how expanding its criteria affected validity. METHODS: We performed a retrospective cohort study at two tertiary care hospitals with one EHR, among adults hospitalized with COVID-19 February 2020-March 2021. We assessed five candidate definitions for ARDS: the EHR-Berlin definition modeled on Berlin criteria, and four alternatives informed by recent proposals to expand criteria and include patients on high-flow oxygen (EHR-Alternative 1), relax imaging criteria (EHR-Alternatives 2-3), and extend timing windows (EHR-Alternative 4). We evaluated two aspects of construct validity for the EHR-Berlin definition: (1) criterion validity: agreement with manual ARDS classification by experts, available in 175 patients; (2) predictive validity: relationships with hospital mortality, assessed by Pearson r and by area under the receiver operating curve (AUROC). We assessed predictive validity and timing of identification of EHR-Berlin definition compared to alternative definitions. RESULTS: Among 765 patients, mean (SD) age was 57 (18) years and 471 (62%) were male. The EHR-Berlin definition classified 171 (22%) patients as ARDS, which had high agreement with manual classification (kappa 0.85), and was associated with mortality (Pearson r = 0.39; AUROC 0.72, 95% CI 0.68, 0.77). In comparison, EHR-Alternative 1 classified 219 (29%) patients as ARDS, maintained similar relationships to mortality (r = 0.40; AUROC 0.74, 95% CI 0.70, 0.79, Delong test P = 0.14), and identified patients earlier in their hospitalization (median 13 vs. 15 h from admission, Wilcoxon signed-rank test P < 0.001). EHR-Alternative 3, which removed imaging criteria, had similar correlation (r = 0.41) but better discrimination for mortality (AUROC 0.76, 95% CI 0.72, 0.80; P = 0.036), and identified patients median 2 h (P < 0.001) from admission. CONCLUSIONS: The EHR-Berlin definition can enable ARDS identification with high criterion validity, supporting large-scale study and surveillance. There are opportunities to expand the Berlin criteria that preserve predictive validity and facilitate earlier identification.

Predicting decompression surgery by applying multimodal deep learning to patients' structured and unstructured health data.

BACKGROUND: Low back pain (LBP) is a common condition made up of a variety of anatomic and clinical subtypes. Lumbar disc herniation (LDH) and lumbar spinal stenosis (LSS) are two subtypes highly associated with LBP. Patients with LDH/LSS are often started with non-surgical treatments and if those are not effective then go on to have decompression surgery. However, recommendation of surgery is complicated as the outcome may depend on the patient's health characteristics. We developed a deep learning (DL) model to predict decompression surgery for patients with LDH/LSS. MATERIALS AND METHOD: We used datasets of 8387 and 8620 patients from a prospective study that collected data from four healthcare systems to predict early (within 2 months) and late surgery (within 12 months after a 2 month gap), respectively. We developed a DL model to use patients' demographics, diagnosis and procedure codes, drug names, and diagnostic imaging reports to predict surgery. For each prediction task, we evaluated the model's performance using classical and generalizability evaluation. For classical evaluation, we split the data into training (80%) and testing (20%). For generalizability evaluation, we split the data based on the healthcare system. We used the area under the curve (AUC) to assess performance for each evaluation. We compared results to a benchmark model (i.e. LASSO logistic regression). RESULTS: For classical performance, the DL model outperformed the benchmark model for early surgery with an AUC of 0.725 compared to 0.597. For late surgery, the DL model outperformed the benchmark model with an AUC of 0.655 compared to 0.635. For generalizability performance, the DL model outperformed the benchmark model for early surgery. For late surgery, the benchmark model outperformed the DL model. CONCLUSIONS: For early surgery, the DL model was preferred for classical and generalizability evaluation. However, for late surgery, the benchmark and DL model had comparable performance. Depending on the prediction task, the balance of performance may shift between DL and a conventional ML method. As a result, thorough assessment is needed to quantify the value of DL, a relatively computationally expensive, time-consuming and less interpretable method.

Rationale and design of the Kidney Precision Medicine Project.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport.

Mutations in the microtubule-associated protein tau (MAPT) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear. A novel variant in MAPT resulting in an alanine to threonine substitution at position 152 (A152T tau) has recently been described as a significant risk factor for both frontotemporal lobar degeneration and Alzheimer's disease. Here we use complementary computational, biochemical, molecular, genetic and imaging approaches in Caenorhabditis elegans and mouse models to interrogate the effects of the A152T variant on tau function. In silico analysis suggests that a threonine at position 152 of tau confers a new phosphorylation site. This finding is borne out by mass spectrometric survey of A152T tau phosphorylation in C. elegans and mouse. Optical pulse-chase experiments of Dendra2-tau demonstrate that A152T tau and phosphomimetic A152E tau exhibit increased diffusion kinetics and the ability to traverse across the axon initial segment more efficiently than wild-type (WT) tau. A C. elegans model of tauopathy reveals that A152T and A152E tau confer patterns of developmental toxicity distinct from WT tau, likely due to differential effects on retrograde axonal transport. These data support a role for phosphorylation of the variant threonine in A152T tau toxicity and suggest a mechanism involving impaired retrograde axonal transport contributing to human neurodegenerative disease.

Forecasting Future Asthma Hospital Encounters of Patients With Asthma in an Academic Health Care System: Predictive Model Development and Secondary Analysis Study.

BACKGROUND: Asthma affects a large proportion of the population and leads to many hospital encounters involving both hospitalizations and emergency department visits every year. To lower the number of such encounters, many health care systems and health plans deploy predictive models to prospectively identify patients at high risk and offer them care management services for preventive care. However, the previous models do not have sufficient accuracy for serving this purpose well. Embracing the modeling strategy of examining many candidate features, we built a new machine learning model to forecast future asthma hospital encounters of patients with asthma at Intermountain Healthcare, a nonacademic health care system. This model is more accurate than the previously published models. However, it is unclear how well our modeling strategy generalizes to academic health care systems, whose patient composition differs from that of Intermountain Healthcare. OBJECTIVE: This study aims to evaluate the generalizability of our modeling strategy to the University of Washington Medicine (UWM), an academic health care system. METHODS: All adult patients with asthma who visited UWM facilities between 2011 and 2018 served as the patient cohort. We considered 234 candidate features. Through a secondary analysis of 82,888 UWM data instances from 2011 to 2018, we built a machine learning model to forecast asthma hospital encounters of patients with asthma in the subsequent 12 months. RESULTS: Our UWM model yielded an area under the receiver operating characteristic curve (AUC) of 0.902. When placing the cutoff point for making binary classification at the top 10% (1464/14,644) of patients with asthma with the largest forecasted risk, our UWM model yielded an accuracy of 90.6% (13,268/14,644), a sensitivity of 70.2% (153/218), and a specificity of 90.91% (13,115/14,426). CONCLUSIONS: Our modeling strategy showed excellent generalizability to the UWM, leading to a model with an AUC that is higher than all of the AUCs previously reported in the literature for forecasting asthma hospital encounters. After further optimization, our model could be used to facilitate the efficient and effective allocation of asthma care management resources to improve outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.5039.

Systematic review of submental artery island flap versus free flap in head and neck reconstruction.

PURPOSE: The aim of this systematic review is to compare the perioperative characteristics and outcomes of submental artery island flap (SAIF) to free tissue transfer (FTT) in head and neck reconstruction. MATERIALS AND METHODS: Screening and data extraction were done with Pubmed, Embase, and Web of Science databases by two independent authors to identify randomized and observational studies that compared patient outcomes for SAIF vs. FTT for reconstruction head and neck cancer ablative surgery. Data were pooled with random-effects meta-analysis to determine pooled difference in means (DM), absolute risk differences, and 95% confidence intervals (CI). Heterogeneity was assessed with the I-squared statistic. RESULTS: Initial query yielded 997 results, of which 7 studies met inclusion criteria. The pooled sample sizes for the SAIF and FTT cohorts were 155 and 198, respectively. SAIF reduced mean operative time by 193 min (95% CI -160 to -227), reduced hospital stay by 2.1 days (95% CI -0.9 to -3.4), and had a smaller flap area of 22.5cm2 (95% CI 6.5 to 38.4). SAIF had a 5% higher incidence of partial flap necrosis than FTT (95% CI, 1 to 10), but all other perioperative complications, including recurrence rate in malignant cases, were statistically comparable. CONCLUSIONS: The SAIF requires less operative time, hospital stay, and has comparable perioperative outcomes to FTT, but the area of flap harvest is significantly smaller. The findings of this study add to the growing body of evidence demonstrating the safety and reliability of SAIF in head and neck reconstruction.

Pathogenicity and functional impact of non-frameshifting insertion/deletion variation in the human genome.

Differentiation between phenotypically neutral and disease-causing genetic variation remains an open and relevant problem. Among different types of variation, non-frameshifting insertions and deletions (indels) represent an understudied group with widespread phenotypic consequences. To address this challenge, we present a machine learning method, MutPred-Indel, that predicts pathogenicity and identifies types of functional residues impacted by non-frameshifting insertion/deletion variation. The model shows good predictive performance as well as the ability to identify impacted structural and functional residues including secondary structure, intrinsic disorder, metal and macromolecular binding, post-translational modifications, allosteric sites, and catalytic residues. We identify structural and functional mechanisms impacted preferentially by germline variation from the Human Gene Mutation Database, recurrent somatic variation from COSMIC in the context of different cancers, as well as de novo variants from families with autism spectrum disorder. Further, the distributions of pathogenicity prediction scores generated by MutPred-Indel are shown to differentiate highly recurrent from non-recurrent somatic variation. Collectively, we present a framework to facilitate the interrogation of both pathogenicity and the functional effects of non-frameshifting insertion/deletion variants. The MutPred-Indel webserver is available at http://mutpred.mutdb.org/.

Evaluation of the secondary use of electronic health records to detect seasonal, holiday-related, and rare events related to traumatic injury and poisoning.

BACKGROUND: The increasing adoption of electronic health record (EHR) systems enables automated, large scale, and meaningful analysis of regional population health. We explored how EHR systems could inform surveillance of trauma-related emergency department visits arising from seasonal, holiday-related, and rare environmental events. METHODS: We analyzed temporal variation in diagnosis codes over 24 years of trauma visit data at the three hospitals in the University of Washington Medicine system in Seattle, Washington, USA. We identified seasons and days in which specific codes and categories of codes were statistically enriched, meaning that a significantly greater than average proportion of trauma visits included a given diagnosis code during that time period. RESULTS: We confirmed known seasonal patterns in emergency department visits for trauma. As expected, cold weather-related incidents (e.g. frostbite, snowboarding injury) were enriched in the winter, whereas fair weather-related incidents (e.g. bug bites, boating accidents, bicycle accidents) were enriched in the spring and summer. Our analysis of specific days of the year found that holidays were enriched for alcohol poisoning, assaults, and firework accidents. We also detected one time regional events such as the 2001 Nisqually earthquake and the 2006 Hanukkah Eve Windstorm. CONCLUSIONS: Though EHR systems were developed to prioritize operational rather than analytic priorities and have consequent limitations for surveillance, our EHR enrichment analysis nonetheless re-identified expected temporal population health patterns. EHRs are potentially a valuable source of information to inform public health policy, both in retrospective analysis and in a surveillance capacity.

Predicting venous thromboembolism risk from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges.

Genetics play a key role in venous thromboembolism (VTE) risk, however established risk factors in European populations do not translate to individuals of African descent because of the differences in allele frequencies between populations. As part of the fifth iteration of the Critical Assessment of Genome Interpretation, participants were asked to predict VTE status in exome data from African American subjects. Participants were provided with 103 unlabeled exomes from patients treated with warfarin for non-VTE causes or VTE and asked to predict which disease each subject had been treated for. Given the lack of training data, many participants opted to use unsupervised machine learning methods, clustering the exomes by variation in genes known to be associated with VTE. The best performing method using only VTE related genes achieved an area under the ROC curve of 0.65. Here, we discuss the range of methods used in the prediction of VTE from sequence data and explore some of the difficulties of conducting a challenge with known confounders. In addition, we show that an existing genetic risk score for VTE that was developed in European subjects works well in African Americans.

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases.

Whole-genome sequencing (WGS) holds great potential as a diagnostic test. However, the majority of patients currently undergoing WGS lack a molecular diagnosis, largely due to the vast number of undiscovered disease genes and our inability to assess the pathogenicity of most genomic variants. The CAGI SickKids challenges attempted to address this knowledge gap by assessing state-of-the-art methods for clinical phenotype prediction from genomes. CAGI4 and CAGI5 participants were provided with WGS data and clinical descriptions of 25 and 24 undiagnosed patients from the SickKids Genome Clinic Project, respectively. Predictors were asked to identify primary and secondary causal variants. In addition, for CAGI5, groups had to match each genome to one of three disorder categories (neurologic, ophthalmologic, and connective), and separately to each patient. The performance of matching genomes to categories was no better than random but two groups performed significantly better than chance in matching genomes to patients. Two of the ten variants proposed by two groups in CAGI4 were deemed to be diagnostic, and several proposed pathogenic variants in CAGI5 are good candidates for phenotype expansion. We discuss implications for improving in silico assessment of genomic variants and identifying new disease genes.

Assessing computational predictions of the phenotypic effect of cystathionine-beta-synthase variants.

Accurate prediction of the impact of genomic variation on phenotype is a major goal of computational biology and an important contributor to personalized medicine. Computational predictions can lead to a better understanding of the mechanisms underlying genetic diseases, including cancer, but their adoption requires thorough and unbiased assessment. Cystathionine-beta-synthase (CBS) is an enzyme that catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine, and in which variations are associated with human hyperhomocysteinemia and homocystinuria. We have created a computational challenge under the CAGI framework to evaluate how well different methods can predict the phenotypic effect(s) of CBS single amino acid substitutions using a blinded experimental data set. CAGI participants were asked to predict yeast growth based on the identity of the mutations. The performance of the methods was evaluated using several metrics. The CBS challenge highlighted the difficulty of predicting the phenotype of an ex vivo system in a model organism when classification models were trained on human disease data. We also discuss the variations in difficulty of prediction for known benign and deleterious variants, as well as identify methodological and experimental constraints with lessons to be learned for future challenges.

Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants.

Testing for variation in BRCA1 and BRCA2 (commonly referred to as BRCA1/2), has emerged as a standard clinical practice and is helping countless women better understand and manage their heritable risk of breast and ovarian cancer. Yet the increased rate of BRCA1/2 testing has led to an increasing number of Variants of Uncertain Significance (VUS), and the rate of VUS discovery currently outpaces the rate of clinical variant interpretation. Computational prediction is a key component of the variant interpretation pipeline. In the CAGI5 ENIGMA Challenge, six prediction teams submitted predictions on 326 newly-interpreted variants from the ENIGMA Consortium. By evaluating these predictions against the new interpretations, we have gained a number of insights on the state of the art of variant prediction and specific steps to further advance this state of the art.

Assessment of predicted enzymatic activity of α-N-acetylglucosaminidase variants of unknown significance for CAGI 2016.

The NAGLU challenge of the fourth edition of the Critical Assessment of Genome Interpretation experiment (CAGI4) in 2016, invited participants to predict the impact of variants of unknown significance (VUS) on the enzymatic activity of the lysosomal hydrolase α-N-acetylglucosaminidase (NAGLU). Deficiencies in NAGLU activity lead to a rare, monogenic, recessive lysosomal storage disorder, Sanfilippo syndrome type B (MPS type IIIB). This challenge attracted 17 submissions from 10 groups. We observed that top models were able to predict the impact of missense mutations on enzymatic activity with Pearson's correlation coefficients of up to .61. We also observed that top methods were significantly more correlated with each other than they were with observed enzymatic activity values, which we believe speaks to the importance of sequence conservation across the different methods. Improved functional predictions on the VUS will help population-scale analysis of disease epidemiology and rare variant association analysis.

Assessing the performance of in silico methods for predicting the pathogenicity of variants in the gene CHEK2, among Hispanic females with breast cancer.

The availability of disease-specific genomic data is critical for developing new computational methods that predict the pathogenicity of human variants and advance the field of precision medicine. However, the lack of gold standards to properly train and benchmark such methods is one of the greatest challenges in the field. In response to this challenge, the scientific community is invited to participate in the Critical Assessment for Genome Interpretation (CAGI), where unpublished disease variants are available for classification by in silico methods. As part of the CAGI-5 challenge, we evaluated the performance of 18 submissions and three additional methods in predicting the pathogenicity of single nucleotide variants (SNVs) in checkpoint kinase 2 (CHEK2) for cases of breast cancer in Hispanic females. As part of the assessment, the efficacy of the analysis method and the setup of the challenge were also considered. The results indicated that though the challenge could benefit from additional participant data, the combined generalized linear model analysis and odds of pathogenicity analysis provided a framework to evaluate the methods submitted for SNV pathogenicity identification and for comparison to other available methods. The outcome of this challenge and the approaches used can help guide further advancements in identifying SNV-disease relationships.

The accuracy of passive phone sensors in predicting daily mood.

BACKGROUND: Smartphones provide a low-cost and efficient means to collect population level data. Several small studies have shown promise in predicting mood variability from smartphone-based sensor and usage data, but have not been generalized to nationally recruited samples. This study used passive smartphone data, demographic characteristics, and baseline depressive symptoms to predict prospective daily mood. METHOD: Daily phone usage data were collected passively from 271 Android phone users participating in a fully remote randomized controlled trial of depression treatment (BRIGHTEN). Participants completed daily Patient Health Questionnaire-2. A machine learning approach was used to predict daily mood for the entire sample and individual participants. RESULTS: Sample-wide estimates showed a marginally significant association between physical mobility and self-reported daily mood (B = -0.04, P < 0.05), but the predictive models performed poorly for the sample as a whole (median R2 ∼ 0). Focusing on individuals, 13.9% of participants showed significant association (FDR < 0.10) between a passive feature and daily mood. Personalized models combining features provided better prediction performance (median area under the curve [AUC] > 0.50) for 80.6% of participants and very strong prediction in a subset (median AUC > 0.80) for 11.8% of participants. CONCLUSIONS: Passive smartphone data with current features may not be suited for predicting daily mood at a population level because of the high degree of intra- and interindividual variation in phone usage patterns and daily mood ratings. Personalized models show encouraging early signs for predicting an individual's mood state changes, with GPS-derived mobility being the top most important feature in the present sample.

Biological and functional relevance of CASP predictions.

Our goal is to answer the question: compared with experimental structures, how useful are predicted models for functional annotation? We assessed the functional utility of predicted models by comparing the performances of a suite of methods for functional characterization on the predictions and the experimental structures. We identified 28 sites in 25 protein targets to perform functional assessment. These 28 sites included nine sites with known ligand binding (holo-sites), nine sites that are expected or suggested by experimental authors for small molecule binding (apo-sites), and Ten sites containing important motifs, loops, or key residues with important disease-associated mutations. We evaluated the utility of the predictions by comparing their microenvironments to the experimental structures. Overall structural quality correlates with functional utility. However, the best-ranked predictions (global) may not have the best functional quality (local). Our assessment provides an ability to discriminate between predictions with high structural quality. When assessing ligand-binding sites, most prediction methods have higher performance on apo-sites than holo-sites. Some servers show consistently high performance for certain types of functional sites. Finally, many functional sites are associated with protein-protein interaction. We also analyzed biologically relevant features from the protein assemblies of two targets where the active site spanned the protein-protein interface. For the assembly targets, we find that the features in the models are mainly determined by the choice of template.

When loss-of-function is loss of function: assessing mutational signatures and impact of loss-of-function genetic variants.

MOTIVATION: Loss-of-function genetic variants are frequently associated with severe clinical phenotypes, yet many are present in the genomes of healthy individuals. The available methods to assess the impact of these variants rely primarily upon evolutionary conservation with little to no consideration of the structural and functional implications for the protein. They further do not provide information to the user regarding specific molecular alterations potentially causative of disease. RESULTS: To address this, we investigate protein features underlying loss-of-function genetic variation and develop a machine learning method, MutPred-LOF, for the discrimination of pathogenic and tolerated variants that can also generate hypotheses on specific molecular events disrupted by the variant. We investigate a large set of human variants derived from the Human Gene Mutation Database, ClinVar and the Exome Aggregation Consortium. Our prediction method shows an area under the Receiver Operating Characteristic curve of 0.85 for all loss-of-function variants and 0.75 for proteins in which both pathogenic and neutral variants have been observed. We applied MutPred-LOF to a set of 1142 de novo vari3ants from neurodevelopmental disorders and find enrichment of pathogenic variants in affected individuals. Overall, our results highlight the potential of computational tools to elucidate causal mechanisms underlying loss of protein function in loss-of-function variants. AVAILABILITY AND IMPLEMENTATION: http://mutpred.mutdb.org. CONTACT: predrag@indiana.edu.

Using Mobile Apps to Assess and Treat Depression in Hispanic and Latino Populations: Fully Remote Randomized Clinical Trial.

BACKGROUND: Most people with mental health disorders fail to receive timely access to adequate care. US Hispanic/Latino individuals are particularly underrepresented in mental health care and are historically a very difficult population to recruit into clinical trials; however, they have increasing access to mobile technology, with over 75% owning a smartphone. This technology has the potential to overcome known barriers to accessing and utilizing traditional assessment and treatment approaches. OBJECTIVE: This study aimed to compare recruitment and engagement in a fully remote trial of individuals with depression who either self-identify as Hispanic/Latino or not. A secondary aim was to assess treatment outcomes in these individuals using three different self-guided mobile apps: iPST (based on evidence-based therapeutic principles from problem-solving therapy, PST), Project Evolution (EVO; a cognitive training app based on cognitive neuroscience principles), and health tips (a health information app that served as an information control). METHODS: We recruited Spanish and English speaking participants through social media platforms, internet-based advertisements, and traditional fliers in select locations in each state across the United States. Assessment and self-guided treatment was conducted on each participant's smartphone or tablet. We enrolled 389 Hispanic/Latino and 637 non-Hispanic/Latino adults with mild to moderate depression as determined by Patient Health Questionnaire-9 (PHQ-9) score≥5 or related functional impairment. Participants were first asked about their preferences among the three apps and then randomized to their top two choices. Outcomes were depressive symptom severity (measured using PHQ-9) and functional impairment (assessed with Sheehan Disability Scale), collected over 3 months. Engagement in the study was assessed based on the number of times participants completed active surveys. RESULTS: We screened 4502 participants and enrolled 1040 participants from throughout the United States over 6 months, yielding a sample of 348 active users. Long-term engagement surfaced as a key issue among Hispanic/Latino participants, who dropped from the study 2 weeks earlier than their non-Hispanic/Latino counterparts (P<.02). No significant differences were observed for treatment outcomes between those identifying as Hispanic/Latino or not. Although depressive symptoms improved (beta=-2.66, P=.006) over the treatment course, outcomes did not vary by treatment app. CONCLUSIONS: Fully remote mobile-based studies can attract a diverse participant pool including people from traditionally underserved communities in mental health care and research (here, Hispanic/Latino individuals). However, keeping participants engaged in this type of "low-touch" research study remains challenging. Hispanic/Latino populations may be less willing to use mobile apps for assessing and managing depression. Future research endeavors should use a user-centered design to determine the role of mobile apps in the assessment and treatment of depression for this population, app features they would be interested in using, and strategies for long-term engagement. TRIAL REGISTRATION: Clinicaltrials.gov NCT01808976; https://clinicaltrials.gov/ct2/show/NCT01808976 (Archived by WebCite at http://www.webcitation.org/70xI3ILkz).