ArticleTwin research and human genetics : the official journal of the International Society for Twin Studies2017
The Weighting is the Hardest Part: On the Behavior of the Likelihood Ratio Test and the Score Test Under a Data-Driven Weighting Scheme in Sequenced Samples.
Article in Twin research and human genetics : the official journal of the International Society for Twin Studies, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.
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Who cites it
5 citing papers in PubMed, 1 synthesis or guideline pooled it, 6 citations in OpenAlex.
- Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder.Translational psychiatry · 2022Pooled it
- Recent advances and challenges of rare variant association analysis in the biobank sequencing era.Frontiers in genetics · 2022Review
- Rare variant association testing in the non-coding genome.Human genetics · 2020Review
- Convex combination sequence kernel association test for rare-variant studies.Genetic epidemiology · 2020Article
- Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-analysis of Noncoding Variation in Metabochip Data.American journal of human genetics · 2017Article
Corrections and comments
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Authors and funding
8 authors at 6 institutions in 3 countries.
Funding
Abstract
Sequence-based association studies are at a critical inflexion point with the increasing availability of exome-sequencing data. A popular test of association is the sequence kernel association test (SKAT). Weights are embedded within SKAT to reflect the hypothesized contribution of the variants to the trait variance. Because the true weights are generally unknown, and so are subject to misspecification, we examined the efficiency of a data-driven weighting scheme. We propose the use of a set of theoretically defensible weighting schemes, of which, we assume, the one that gives the largest test statistic is likely to capture best the allele frequency-functional effect relationship. We show that the use of alternative weights obviates the need to impose arbitrary frequency thresholds. As both the score test and the likelihood ratio test (LRT) may be used in this context, and may differ in power, we characterize the behavior of both tests. The two tests have equal power, if the weights in the set included weights resembling the correct ones. However, if the weights are badly specified, the LRT shows superior power (due to its robustness to misspecification). With this data-driven weighting procedure the LRT detected significant signal in genes located in regions already confirmed as associated with schizophrenia - the PRRC2A (p = 1.020e-06) and the VARS2 (p = 2.383e-06) - in the Swedish schizophrenia case-control cohort of 11,040 individuals with exome-sequencing data. The score test is currently preferred for its computational efficiency and power. Indeed, assuming correct specification, in some circumstances, the score test is the most powerful test. However, LRT has the advantageous properties of being generally more robust and more powerful under weight misspecification. This is an important result given that, arguably, misspecified models are likely to be the rule rather than the exception in weighting-based approaches.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.