Matthew S. Lebo

Human Proteome-wide Mechanistic Interpretation of Missense Variants through Protein Feature Enrichment Score

PFES quantifies the protein context of missense variants, enabling mechanistically transparent interpretation and reclassification of variants of uncertain significance.

Language models reveal evidence gaps in variants of uncertain significance

The paper uses language models to analyze ClinVar variant summaries, identifying evidence gaps in Variants of Uncertain Significance and reclassifying some as likely benign or pathogenic.

Extracting and calibrating evidence of variant pathogenicity from population biobank data

The paper uses population biobank data to identify and calibrate evidence of variant pathogenicity for 41 genes, finding that 2.6% of participants have rare variants with moderate or stronger evidence of pathogenicity.

Distinct rates of VUS reclassification are observed when subclassifying VUS by evidence level

The paper examines how variants of uncertain significance (VUS) are reclassified based on subclassification evidence levels across four clinical laboratories.

Decoding Genetics, Ancestry, and Geospatial Context for Precision Health

The paper analyzes genetic, ancestral, and geospatial data from a biobank to explore their relationships with health outcomes in a historically diverse population.

The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

The paper analyzes VUS rates in genetic testing and finds lower rates in exome/genome sequencing compared to multi-gene panels, suggesting improvements in variant reporting practices.

Informing Variant Assessment using Structured Evidence from Prior Classifications (PS1, PM5, and PVS1 Sequence Variant Interpretation Criteria)

The paper uses prior ClinVar variant classifications to inform ACMG/AMP variant interpretation by identifying SNVs with similar functional consequences to pathogenic variants.

Validation of a Trans-Ancestry Polygenic Risk Score for Type 2 Diabetes in Diverse Populations

This paper develops a trans-ancestry polygenic risk score for type 2 diabetes and validates it across diverse populations to improve equitable risk prediction.

Medical Evaluation of Unanticipated Monogenic Disease Risks Identified through Newborn Genomic Screening: Findings from the BabySeq Project

The paper evaluates unanticipated monogenic disease risks found in newborns through genomic screening, finding most risks are actionable and lead to medical interventions.

Returning Actionable Genomic Results in a Research Biobank: Analytic Validity, Clinical Implementation and Resource Utilization

This study evaluates the feasibility and costs of returning actionable genomic results from a biobank, finding high false positive rates in genotyping and significant under-testing among at-risk individuals.

A framework for integrated clinical risk assessment using population sequencing data

This paper integrates monogenic, polygenic, and clinical risk factors to predict disease risk for carriers of rare variants, identifying elevated risk in 18.22% of UK Biobank participants for breast cancer, familial hypercholesterolemia, and colorectal cancer.

A Framework for Automated Gene Selection in Genomic Screening

This paper proposes a framework for automated gene selection in genomic screening, creating gene lists with strong disease associations and demonstrating their utility in healthy genome screening.

Prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test

This study compares genome sequencing with standard-of-care genetic testing, finding similar diagnostic yields but longer turnaround times for genome sequencing.

Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer

The paper investigates the association between age-related mosaic chromosomal alterations and infection risk in 767,891 individuals without blood cancer, finding increased infection susceptibility linked to mCAs.

Polygenic background modifies penetrance of monogenic variants conferring risk for coronary artery disease, breast cancer, or colorectal cancer

The paper examines how polygenic risk modifies the penetrance of monogenic variants in coronary artery disease, breast cancer, and colorectal cancer across multiple cohorts.

Genetic variant pathogenicity prediction trained using disease-specific clinical sequencing datasets

The paper introduces a disease-specific variant pathogenicity predictor trained on clinical sequencing data from cardiomyopathy, epilepsy, and RASopathies patients.

Considerations for clinical curation, classification and reporting of low-penetrance and low effect size variants associated with disease risk

The paper proposes a framework for classifying and reporting low-penetrance variants associated with disease risk, emphasizing data elements and criteria for clinical inclusion.

A Rigorous Interlaboratory Examination of the Need to Confirm NGS-Detected Variants by an Orthogonal Method in Clinical Genetic Testing

The paper examines the need for orthogonal confirmation of NGS-detected variants in clinical testing and develops criteria to identify false positives with high accuracy.

A Model for Genome-First Care: Returning Secondary Genomic Findings to Participants and Their Healthcare Providers in a Large Research Cohort

The paper describes a model for returning secondary genomic findings to participants and healthcare providers in a large research cohort, with 93% successful contact rates and 222 providers notified.