Revisiting the Wald Test in Small Case-Control Studies With a Skewed Covariate.

The Wald test is routinely used in case-control studies to test for association between a covariate and disease. However, when the evidence for association is high, the Wald test tends to inflate small P values as a result of the Hauck-Donner effect (HDE). Here, we investigate the HDE in the context of genetic burden, both with and without additional covariates. First, we examine the burden-based P values in the absence of association using whole-exome sequence data from 1000 Genomes Project reference samples (n = 54) and selected preterm infants with neonatal complications (n = 74). Our careful analysis of the burden-based P values shows that the HDE is present and that the cause of the HDE in this setting is likely a natural extension of the well-known cause of the HDE in 2 × 2 contingency tables. Second, in a reanalysis of real data, we find that the permutation test provides increased power over the Wald, Firth, and likelihood ratio tests, which agrees with our intuition since the permutation test is valid for any sample size and since it does not suffer from the HDE. Therefore, we propose a powerful and computationally efficient permutation-based approach for the analysis and reanalysis of small case-control association studies.

Prediction of short-term neonatal complications in preterm infants using exome-wide genetic variation and gestational age: a pilot study.

BACKGROUND: Preterm birth is the leading cause of mortality and morbidity in young children, with over a million deaths per year worldwide arising from neonatal complications (NCs). NCs are moderately heritable although the genetic causes are largely unknown. Therefore, we investigated the impact of accumulated genetic variation (burden) on NCs in non-Hispanic White (NHW) and non-Hispanic Black (NHB) preterm infants. METHODS: We sequenced 182 exomes from infants with gestational ages from 26 to 31 weeks. These infants were cared for in the same time period and hospital environment. Eighty-one preterm infants did not develop NCs, whereas 101 developed at least one severe complication. We measured the effect of burden at the single-gene and exome-wide levels and derived a polygenic risk score (PRS) from the top 10 genes to predict NCs. RESULTS: Burden across the exome was associated with NCs in NHW (p = 0.05) preterm infants suggesting that multiple genes influence susceptibility. In a post hoc analysis, we find that PRS alone predicts NCs (AUC = 0.67) and that PRS is uncorrelated with GA ([Formula: see text] = 0.05; p = 0.53). When PRS and GA at birth are combined, the AUC is 0.87. CONCLUSIONS: Our results support the hypothesis that genetic burden influences NCs in NHW preterm infants.