R01HD105256

Trio Analysis of Recurrent Pregnancy Loss Integrated Bioinformatics Genomics Study (TRIOS) - Project Summary

Recurrent pregnancy loss (RPL) affects up to 5% of couples, yet nearly half of cases remain unexplained by current testing recommendations. Euploid pregnancy loss, in the setting of unexplained RPL, is particularly frustrating for patients and providers because there is no clear explanation or any proven therapies to mitigate the risk of subsequent miscarriages. As clinical presentation and subsequent pregnancy outcomes vary widely, this complex disorder will ultimately require a precision health approach.

While more than 3000 human genes are conserved and likely essential for early development, remarkably little is known about their contribution to RPL, and current genetic databases are essentially devoid of RPL entries. Moreover, there is currently no database that annotates phenotypes and genotypes of these essential genes. This proposal aims to define the genetic determinants of RPL through clinical and molecular phenotyping and genomic sequencing of a large RPL cohort, combined with novel bioinformatics and machine learning approaches to derive predictive risk algorithms.

A comprehensive approach to identify genomic markers of pregnancy loss by whole genome sequencing of well-characterized RPL trios (mother-father-pregnancy loss) will be undertaken in Aim 1. These genetics efforts will be paired in Aim 2 with metabolomic, lipidomic, and single-cell transcriptomic profiling preconception and in early pregnancy. Leveraged with innovative machine learning strategies in Aim 3, this approach will significantly advance understanding of the genetic underpinnings of unexplained RPL.

A clinical 'intolerome' database will be constructed in Aim 4 to facilitate worldwide collaboration and curation of genotypes and associated phenotypes, making the genetics and omics data and results available to the public as well as other funded teams. This multidisciplinary team includes leaders in RPL, genetics, genomics, prenatal diagnosis, bioinformatics, and machine learning at Stanford, UCSF, and OHSU. Combined, we have a substantial cohort of RPL patients that will serve as a robust recruitment source, along with a collaboration with the unique UK Pregnancy Baby Biobank of existing trios to accomplish project goals.

The proposed study is anticipated to have significant clinical and research impact by identifying the genomic contribution to RPL in a large and well-phenotyped cohort and building improved risk predictions based on machine learning incorporating clinical, genetic, and molecular data. This work will lay the foundation for precision medicine-based interventions for RPL couples who are difficult to diagnose and have few proven treatments.

The Leland Stanford Junior University

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Sunnyvale, California 940873832 United States

Single Zip Code

Genomic Predictors of Pregnancy Loss (R01 Clinical Trial Not Allowed) (RFA-HD-21-005)

Amendment Since initial award the total obligations have increased 380% from $1,466,398 to $7,034,759.