Dataset Information

ADuLT: An efficient and robust time-to-event GWAS.

ABSTRACT: Proportional hazards models have been proposed to analyse time-to-event phenotypes in genome-wide association studies (GWAS). However, little is known about the ability of proportional hazards models to identify genetic associations under different generative models and when ascertainment is present. Here we propose the age-dependent liability threshold (ADuLT) model as an alternative to a Cox regression based GWAS, here represented by SPACox. We compare ADuLT, SPACox, and standard case-control GWAS in simulations under two generative models and with varying degrees of ascertainment as well as in the iPSYCH cohort. We find Cox regression GWAS to be underpowered when cases are strongly ascertained (cases are oversampled by a factor 5), regardless of the generative model used. ADuLT is robust to ascertainment in all simulated scenarios. Then, we analyse four psychiatric disorders in iPSYCH, ADHD, Autism, Depression, and Schizophrenia, with a strong case-ascertainment. Across these psychiatric disorders, ADuLT identifies 20 independent genome-wide significant associations, case-control GWAS finds 17, and SPACox finds 8, which is consistent with simulation results. As more genetic data are being linked to electronic health records, robust GWAS methods that can make use of age-of-onset information will help increase power in analyses for common health outcomes.

SUBMITTER: Pedersen EM

PROVIDER: S-EPMC10492844 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ADuLT: An efficient and robust time-to-event GWAS.

Pedersen Emil M EM Agerbo Esben E Plana-Ripoll Oleguer O Steinbach Jette J Krebs Morten D MD Hougaard David M DM Werge Thomas T Nordentoft Merete M Børglum Anders D AD Musliner Katherine L KL Ganna Andrea A Schork Andrew J AJ Mortensen Preben B PB McGrath John J JJ Privé Florian F Vilhjálmsson Bjarni J BJ

Nature communications 20230909 1

Proportional hazards models have been proposed to analyse time-to-event phenotypes in genome-wide association studies (GWAS). However, little is known about the ability of proportional hazards models to identify genetic associations under different generative models and when ascertainment is present. Here we propose the age-dependent liability threshold (ADuLT) model as an alternative to a Cox regression based GWAS, here represented by SPACox. We compare ADuLT, SPACox, and standard case-control ...[more]

PMID: 37689771

Similar Datasets

Project description:Bioacoustic sensors, sometimes known as autonomous recording units (ARUs), can record sounds of wildlife over long periods of time in scalable and minimally invasive ways. Deriving per-species abundance estimates from these sensors requires detection, classification, and quantification of animal vocalizations as individual acoustic events. Yet, variability in ambient noise, both over time and across sensors, hinders the reliability of current automated systems for sound event detection (SED), such as convolutional neural networks (CNN) in the time-frequency domain. In this article, we develop, benchmark, and combine several machine listening techniques to improve the generalizability of SED models across heterogeneous acoustic environments. As a case study, we consider the problem of detecting avian flight calls from a ten-hour recording of nocturnal bird migration, recorded by a network of six ARUs in the presence of heterogeneous background noise. Starting from a CNN yielding state-of-the-art accuracy on this task, we introduce two noise adaptation techniques, respectively integrating short-term (60 ms) and long-term (30 min) context. First, we apply per-channel energy normalization (PCEN) in the time-frequency domain, which applies short-term automatic gain control to every subband in the mel-frequency spectrogram. Secondly, we replace the last dense layer in the network by a context-adaptive neural network (CA-NN) layer, i.e. an affine layer whose weights are dynamically adapted at prediction time by an auxiliary network taking long-term summary statistics of spectrotemporal features as input. We show that PCEN reduces temporal overfitting across dawn vs. dusk audio clips whereas context adaptation on PCEN-based summary statistics reduces spatial overfitting across sensor locations. Moreover, combining them yields state-of-the-art results that are unmatched by artificial data augmentation alone. We release a pre-trained version of our best performing system under the name of BirdVoxDetect, a ready-to-use detector of avian flight calls in field recordings.

Project description:ObjectiveWe developed and evaluated a privacy-preserving One-shot Distributed Algorithm to fit a multicenter Cox proportional hazards model (ODAC) without sharing patient-level information across sites.Materials and methodsUsing patient-level data from a single site combined with only aggregated information from other sites, we constructed a surrogate likelihood function, approximating the Cox partial likelihood function obtained using patient-level data from all sites. By maximizing the surrogate likelihood function, each site obtained a local estimate of the model parameter, and the ODAC estimator was constructed as a weighted average of all the local estimates. We evaluated the performance of ODAC with (1) a simulation study and (2) a real-world use case study using 4 datasets from the Observational Health Data Sciences and Informatics network.ResultsOn the one hand, our simulation study showed that ODAC provided estimates nearly the same as the estimator obtained by analyzing, in a single dataset, the combined patient-level data from all sites (ie, the pooled estimator). The relative bias was <0.1% across all scenarios. The accuracy of ODAC remained high across different sample sizes and event rates. On the other hand, the meta-analysis estimator, which was obtained by the inverse variance weighted average of the site-specific estimates, had substantial bias when the event rate is <5%, with the relative bias reaching 20% when the event rate is 1%. In the Observational Health Data Sciences and Informatics network application, the ODAC estimates have a relative bias <5% for 15 out of 16 log hazard ratios, whereas the meta-analysis estimates had substantially higher bias than ODAC.ConclusionsODAC is a privacy-preserving and noniterative method for implementing time-to-event analyses across multiple sites. It provides estimates on par with the pooled estimator and substantially outperforms the meta-analysis estimator when the event is uncommon, making it extremely suitable for studying rare events and diseases in a distributed manner.

Dataset Information

ADuLT: An efficient and robust time-to-event GWAS.

Publications

ADuLT: An efficient and robust time-to-event GWAS.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets