ABSTRACT
When quantitative longitudinal traits are risk factors for disease progression and subject to random biological variation, joint model analysis of time-to-event and longitudinal traits can effectively identify direct and/or indirect genetic association of single nucleotide polymorphisms (SNPs) with time-to-event. We present a joint model that integrates: (1) a multivariate linear mixed model describing trajectories of multiple longitudinal traits as a function of time, SNP effects, and subject-specific random effects and (2) a frailty Cox survival model that depends on SNPs, longitudinal trajectory effects, and subject-specific frailty accounting for dependence among multiple time-to-event traits. Motivated by complex genetic architecture of type 1 diabetes complications (T1DC) observed in the Diabetes Control and Complications Trial (DCCT), we implement a 2-stage approach to inference with bootstrap joint covariance estimation and develop a hypothesis testing procedure to classify direct and/or indirect SNP association with each time-to-event trait. By realistic simulation study, we show that joint modeling of 2 time-to-T1DC (retinopathy and nephropathy) and 2 longitudinal risk factors (HbA1c and systolic blood pressure) reduces estimation bias in genetic effects and improves classification accuracy of direct and/or indirect SNP associations, compared to methods that ignore within-subject risk factor variability and dependence among longitudinal and time-to-event traits. Through DCCT data analysis, we demonstrate feasibility for candidate SNP modeling and quantify effects of sample size and Winner's curse bias on classification for 2 SNPs identified as having indirect associations with time-to-T1DC traits. Joint analysis of multiple longitudinal and multiple time-to-event traits provides insight into complex traits architecture.
Subject(s)
Frailty , Humans , Genome-Wide Association Study/methods , Phenotype , Risk Factors , Disease Progression , Polymorphism, Single NucleotideABSTRACT
A greater number of dairy economic selection indexes are incorporating a measure of feed efficiency (FE) as a key trait. Definitions of FE traits have ranged from dry matter intake (DMI) to residual feed intake (RFI), noting that RFI is effectively DMI adjusted for various energy sink traits such as body weight (BW) and milk energy (MilkE). Other definitions of FE fall between these 2 extremes such as feed saved (FS), which combines RFI and the portion of DMI required to maintain BW. The choice between different FE traits can create confusion as to how to meaningfully compare their heritabilities, estimated breeding values (EBV) and their corresponding reliabilities, and how to differentially incorporate these EBV into selection indexes. If RFI and FS are merely linear functions of DMI, BW, and MilkE with known genetic variances and covariances between these 3 traits, there may be no need to directly compute RFI or FS phenotypes to determine their heritabilities, genetic correlations, EBV, and respective reliabilities for individual animals. We demonstrate how the estimated total genetic merit is invariant to the specification of a FE trait within a selection index. That is, economic weights for a selection index involving one particular FE trait readily convert into the economic weights for a selection index involving a different linear function of that FE trait. We use these different specifications of FE to provide insight as to the effect of the degree of missingness (e.g., paucity of DMI relative to milk yield records) on the EBV accuracies of the various derivative FE traits. We particularly highlight that the generally observed higher EBV accuracies for DMI, then for FS, and lastly for RFI are partly driven by the greater genetic correlations of DMI with BW and MilkE and of FS with BW. Finally, we advocate a genetic regression approach to deriving FS and RFI recognizing that genetic versus residual relationships between FE component traits may differ substantially from each other.