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Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.

ABSTRACT: Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

SUBMITTER: Corbin LJ

PROVIDER: S-EPMC5818506 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.

Corbin Laura J LJ Tan Vanessa Y VY Hughes David A DA Wade Kaitlin H KH Paul Dirk S DS Tansey Katherine E KE Butcher Frances F Dudbridge Frank F Howson Joanna M JM Jallow Momodou W MW John Catherine C Kingston Nathalie N Lindgren Cecilia M CM O'Donavan Michael M O'Rahilly Stephen S Owen Michael J MJ Palmer Colin N A CNA Pearson Ewan R ER Scott Robert A RA van Heel David A DA Whittaker John J Frayling Tim T Tobin Martin D MD Wain Louise V LV Smith George Davey GD Evans David M DM Karpe Fredrik F McCarthy Mark I MI Danesh John J Franks Paul W PW Timpson Nicholas J NJ

Nature communications 20180219 1

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. W ...[more]

PMID: 29459775

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Project description:Childhood asthma is characterized by disparities in the experience of morbidity, including the risk for readmission to the hospital after an initial hospitalization. African American children have been shown to have more than 2 times the hazard of readmission when compared with their white counterparts.To explain why African American children are at greater risk for asthma-related readmissions than white children.This study was completed as part of the Greater Cincinnati Asthma Risks Study, a population-based, prospective, observational cohort. From August 2010 to October 2011, it enrolled 695 children, aged 1 to 16 years, admitted for asthma or wheezing who identified as African American (n?=?441) or white (n?=?254) in an inpatient setting of an urban, tertiary care children's hospital.The main outcome was time to asthma-related readmission and race was the predictor. Biologic, environmental, disease management, access, and socioeconomic hardship variables were measured; their roles in understanding racial readmission disparities were conceptualized using a directed acyclic graphic. Inverse probability of treatment weighting balanced African American and white children with respect to key measured variables. Racial differences in readmission hazard were assessed using weighted Cox proportional hazards regression and Kaplan-Meier curves.The sample was 65% male (n?=?450), and the median age was 5.4 years. African American children were 2.26 times more likely to be readmitted than white children (95% CI, 1.56-3.26). African American children significantly differed with respect to nearly every measured biologic, environmental, disease management, access, and socioeconomic hardship variable. Socioeconomic hardship variables explained 53% of the observed disparity (hazard ratio, 1.47; 95% CI, 1.05-2.05). The addition of biologic, environmental, disease management, and access variables resulted in 80% of the readmission disparity being explained. The difference between African American and white children with respect to readmission hazard no longer reached the level of significance (hazard ratio, 1.18; 95% CI, 0.87-1.60; Cox P?=?.30 and log-rank P?=?.39).A total of 80% of the observed readmission disparity between African American and white children could be explained after statistically balancing available biologic, environmental, disease management, access to care, and socioeconomic and hardship variables across racial groups. Such a comprehensive, well-framed approach to exposures that are associated with morbidity is critical as we attempt to better understand and lessen persistent child asthma disparities.

Project description:BackgroundDDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.MethodsWe carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions.ResultsEighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants.LimitationsSample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder.ConclusionThis study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.

Dataset Information

Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.

Publications

Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.

Similar Datasets

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