Get access

Power of IRT in GWAS: Successful QTL Mapping of Sum Score Phenotypes Depends on Interplay Between Risk Allele Frequency, Variance Explained by the Risk Allele, and Test Characteristics


Correspondence to: Stéphanie M. van den Berg, Department of Research Methodology, Faculty of Behavioral Sciences, University of Twente, Measurement and Data Analysis (OMD), P.O. Box 217, 7500 AE Enschede, The Netherlands. E-mail:


As data from sequencing studies in humans accumulate, rare genetic variants influencing liability to disease and disorders are expected to be identified. Three simulation studies show that characteristics and properties of diagnostic instruments interact with risk allele frequency to affect the power to detect a quantitative trait locus (QTL) based on a test score derived from symptom counts or questionnaire items. Clinical tests, that is, tests that show a positively skewed phenotypic sum score distribution in the general population, are optimal to find rare risk alleles of large effect. Tests that show a negatively skewed sum score distribution are optimal to find rare protective alleles of large effect. For alleles of small effect, tests with normally distributed item parameters give best power for a wide range of allele frequencies. The item-response theory framework can help understand why an existing measurement instrument has more power to detect risk alleles with either low or high frequency, or both kinds.