Figure 4.

Independent filtering for human phenotype ontology

Independent filtering for HPO (IF-HPO) removes hypotheses (here, HPO terms) by criteria independent of the test statistic to reduce the multiple testing burden and boost power. The HPO has a hierarchical structure going from general to specific terms. (1) IF-HPO does not test the top two levels of the HPO under the Phenotypic abnormality root or the terms that are not descendants of the Phenotypic abnormality under the assumption that more specific terms are of higher medical and scientific interest and the signal is likely to be driven by a more specific clinical manifestation. (2) Terms are not tested if they have the exact same counts as one of their child terms, because in this case the annotations of the parent term are derived entirely from those of the child term by the true path rule. (3) Terms are not tested if the coverage is less than 40% of the entire cohort (assuming a cohort of 100 individuals in the figure), under the assumption that the result would not be representative of the cohort. (4) Terms are not tested if the total count is below a threshold for reaching the nominal statistical power. (5) Finally, terms are not tested if one of the genotype classes has neither present nor excluded observations.