Detecting multiple replicating signals using adaptive filtering procedures

Wang, Jingshu; Gui, Lin; Su, Weijie; Sabatti, Chiara; Owen, Art B.

doi:10.1214/21-aos2139

Cited by 7 publications

(16 citation statements)

References 37 publications

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“…We see in Figure 1 that RepFdr often does not control its FDR below the nominal level, and apart from RepFdr, ScreenDMT retains the most power across the scenarios. We also see that DMT has more power than the approach adapted from Pearson (14,20), which helps explain ScreenDMT's power advantage over AdaFilter. We perform the analogous simulation for FWER using methods that account for directionality and provide FWER in Figure S1.…”

Section: Development and Validation Of Screendmtmentioning

confidence: 66%

“…The copyright holder for this preprint (which this version posted July 14, 2023. ; https://doi.org/10.1101/2023.07.12.548737 doi: bioRxiv preprint based multiple testing adjustment is very slightly too strong, but this is where the DMT p-value, like similar statistical tests, is weak anyway. Like in AdaFilter (14), theoretical control of the FWER requires independence of p-values within each study, while control of the FDR for a large number of analytes allows weak dependence between analytes. Such weak dependence typically holds, for example, between gene loci and expression (14).…”

Section: Development and Validation Of Screendmtmentioning

confidence: 99%

“…Like in AdaFilter (14), theoretical control of the FWER requires independence of p-values within each study, while control of the FDR for a large number of analytes allows weak dependence between analytes. Such weak dependence typically holds, for example, between gene loci and expression (14). Importantly, not all FDR methods theoretically allow dependence, such as RepFdr (16).…”

Section: Development and Validation Of Screendmtmentioning

confidence: 99%

“…We compare ScreenDMT's FDR and power via simulation against competing directional replication methods, including the directional approaches of AdaFilter (14), radjustsym (15), RepFdr (16), and DMT (Figure 1). We also compare against a directional alternative to the MaxP test that was adapted from a meta-analysis due to Pearson (14,20), which applies MaxP for each analyte to right-sided p-values of both studies, then applies MaxP to left-sided p-values, and doubles the minimum from the two applications. This procedure also underlies AdaFilter's directional approach.…”

Section: Development and Validation Of Screendmtmentioning

confidence: 99%

“…We improved MaxP's adjusted p-values by developing ScreenMin (13), which reduces the multiple testing burden by filtering out analytes whose minimum p-value is so weak that their MaxP p-value could never be significant. This idea was further developed in AdaFilter (14), which also proposes a method to account for direction. There are other methods that improve upon MaxP adjusted p-values and can account for direction, such as radjust-sym (15), where analytes with strong p-values from each study are selected and only analytes selected from both studies are tested for replicability, and the empirical Bayesian method RepFdr (16).…”

Section: Introductionmentioning

confidence: 99%

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ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Dreyfuss

Djordjilović

Hui

et al. 2023

Preprint

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Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. An activator of BAT is 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with body mass index (BMI) and which directly improves metabolism in other tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro. ScreenDMT can be applied to test directional replication, directional mediation, and qualitative interactions, and our results identify 9,10-diHOME and the pathway stimulated by linoleic acid diols as candidate therapeutic targets to improve systemic metabolism.

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Section: Development and Validation Of Screendmtmentioning

confidence: 66%

Section: Development and Validation Of Screendmtmentioning

confidence: 99%

Section: Development and Validation Of Screendmtmentioning

confidence: 99%

Section: Development and Validation Of Screendmtmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Dreyfuss

Djordjilović

Hui

et al. 2023

Preprint

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Combining Partial True Discovery Guarantee Procedures

Xu,

Solari,

Goeman

2024

Biometrical J

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Closed testing has recently been shown to be optimal for simultaneous true discovery proportion control. It is, however, challenging to construct true discovery guarantee procedures in such a way that it focuses power on some feature sets chosen by users based on their specific interest or expertise. We propose a procedure that allows users to target power on prespecified feature sets, that is, “focus sets.” Still, the method also allows inference for feature sets chosen post hoc, that is, “nonfocus sets,” for which we deduce a true discovery lower confidence bound by interpolation. Our procedure is built from partial true discovery guarantee procedures combined with Holm's procedure and is a conservative shortcut to the closed testing procedure. A simulation study confirms that the statistical power of our method is relatively high for focus sets, at the cost of power for nonfocus sets, as desired. In addition, we investigate its power property for sets with specific structures, for example, trees and directed acyclic graphs. We also compare our method with AdaFilter in the context of replicability analysis. The application of our method is illustrated with a gene ontology analysis in gene expression data.

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ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx

Dreyfuss,

Djordjilović,

Pan

et al. 2024

Commun Biol

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Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids’ association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

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Detecting multiple replicating signals using adaptive filtering procedures

Cited by 7 publications

References 37 publications

ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Combining Partial True Discovery Guarantee Procedures

ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx

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