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A shortcut for multiple testing on the directed acyclic graph of gene ontology.

ABSTRACT: BACKGROUND: Gene set testing has become an important analysis technique in high throughput microarray and next generation sequencing studies for uncovering patterns of differential expression of various biological processes. Often, the large number of gene sets that are tested simultaneously require some sort of multiplicity correction to account for the multiplicity effect. This work provides a substantial computational improvement to an existing familywise error rate controlling multiplicity approach (the Focus Level method) for gene set testing in high throughput microarray and next generation sequencing studies using Gene Ontology graphs, which we call the Short Focus Level. RESULTS: The Short Focus Level procedure, which performs a shortcut of the full Focus Level procedure, is achieved by extending the reach of graphical weighted Bonferroni testing to closed testing situations where restricted hypotheses are present, such as in the Gene Ontology graphs. The Short Focus Level multiplicity adjustment can perform the full top-down approach of the original Focus Level procedure, overcoming a significant disadvantage of the otherwise powerful Focus Level multiplicity adjustment. The computational and power differences of the Short Focus Level procedure as compared to the original Focus Level procedure are demonstrated both through simulation and using real data. CONCLUSIONS: The Short Focus Level procedure shows a significant increase in computation speed over the original Focus Level procedure (as much as ~15,000 times faster). The Short Focus Level should be used in place of the Focus Level procedure whenever the logical assumptions of the Gene Ontology graph structure are appropriate for the study objectives and when either no a priori focus level of interest can be specified or the focus level is selected at a higher level of the graph, where the Focus Level procedure is computationally intractable.

SUBMITTER: Saunders G

PROVIDER: S-EPMC4232707 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A shortcut for multiple testing on the directed acyclic graph of gene ontology.

Saunders Garrett G Stevens John R JR Isom S Clay SC

BMC bioinformatics 20141101

<h4>Background</h4>Gene set testing has become an important analysis technique in high throughput microarray and next generation sequencing studies for uncovering patterns of differential expression of various biological processes. Often, the large number of gene sets that are tested simultaneously require some sort of multiplicity correction to account for the multiplicity effect. This work provides a substantial computational improvement to an existing familywise error rate controlling multipl ...[more]

PMID: 25366961

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Project description:BackgroundHigh tibial osteotomy (HTO) is increasingly used in young and physically active patients with knee osteoarthritis. These patients have high expectations, including return to sport (RTS). By retaining native knee structures, a return to highly knee-demanding activities seems possible. However, evidence on patient-related outcomes, including RTS, is sparse. Also, time to RTS has never been described. Furthermore, prognostic factors for RTS after HTO have never been investigated. These data may further justify HTO as a surgical alternative to knee arthroplasty.PurposeTo investigate the extent and timing of RTS after HTO in the largest cohort investigated for RTS to date and to identify prognostic factors for successful RTS.Study designCase-control study; Level of evidence, 3.MethodsConsecutive patients with HTO, operated on between 2012 and 2015, received a questionnaire. First, pre- and postoperative sports participation questions were asked. Also, time to RTS, sports level and frequency, impact level, the presymptomatic and postoperative Tegner activity score (1-10; higher is more active), and the postoperative Lysholm score (0-100; higher is better) were collected. Finally, prognostic factors for RTS were analyzed using a logistic regression model. Covariates were selected based on univariate analysis and a directed acyclic graph.ResultsWe included 340 eligible patients of whom 294 sufficiently completed the questionnaire. The mean follow-up was 3.7 years (± 1.0 years). Out of 256 patients participating in sports preoperatively, 210 patients (82%) returned to sport postoperatively, of whom 158 (75%) returned within 6 months. We observed a shift to participation in lower-impact activities, although 44% of reported sports activities at final follow-up were intermediate- or high-impact sports. The median Tegner score decreased from 5.0 (interquartile range [IQR], 4.0-6.0) presymptomatically to 4.0 (IQR, 3.0-4.0) at follow-up (P < .001). The mean Lysholm score at follow-up was 68 (SD, ± 22). No significant differences were found between patients with varus or valgus osteoarthritis. The strongest prognostic factor for RTS was continued sports participation in the year before surgery (odds ratio, 2.81; 95% CI, 1.37-5.76).ConclusionMore than 8 of 10 patients returned to sport after HTO. Continued preoperative sports participation was associated with a successful RTS. Future studies need to identify additional prognostic factors.

Dataset Information

A shortcut for multiple testing on the directed acyclic graph of gene ontology.

Publications

A shortcut for multiple testing on the directed acyclic graph of gene ontology.

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