Sum-based global tests are highly popular in multiple hypothesis testing. In this paper, we propose a general closed testing procedure for sum tests, which provides lower confidence bounds for the... Show moreSum-based global tests are highly popular in multiple hypothesis testing. In this paper, we propose a general closed testing procedure for sum tests, which provides lower confidence bounds for the proportion of true discoveries (TDPs), simultaneously over all subsets of hypotheses. These simultaneous inferences come for free, i.e., without any adjustment of the α-level, whenever a global test is used. Our method allows for an exploratory approach, as simultaneity ensures control of the TDP even when the subset of interest is selected post hoc. It adapts to the unknown joint distribution of the data through permutation testing. Any sum test may be employed, depending on the desired power properties. We present an iterative shortcut for the closed testing procedure, based on the branch and bound algorithm, which converges to the full closed testing results, often after few iterations; even if it is stopped early, it controls the TDP. We compare the properties of different choices for the sum test through simulations, then we illustrate the feasibility of the method for high-dimensional data on brain imaging and genomics data. Show less
We propose a permutation-based method for testing a large collection of hypotheses simultaneously. Our method provides lower bounds for the number of true discoveries in any selected subset of... Show moreWe propose a permutation-based method for testing a large collection of hypotheses simultaneously. Our method provides lower bounds for the number of true discoveries in any selected subset of hypotheses. These bounds are simultaneously valid with high confidence. The methodology is particularly useful in functional Magnetic Resonance Imaging cluster analysis, where it provides a confidence statement on the percentage of truly activated voxels within clusters of voxels, avoiding the well-known spatial specificity paradox. We offer a user-friendly tool to estimate the percentage of true discoveries for each cluster while controlling the family-wise error rate for multiple testing and taking into account that the cluster was chosen in a data-driven way. The method adapts to the spatial correlation structure that characterizes functional Magnetic Resonance Imaging data, gaining power over parametric approaches. Show less
We propose a permutation-based method for testing a large collection of hypotheses simultaneously. Our method provides lower bounds for the number of true discoveries in any selected subset of... Show moreWe propose a permutation-based method for testing a large collection of hypotheses simultaneously. Our method provides lower bounds for the number of true discoveries in any selected subset of hypotheses. These bounds are simultaneously valid with high confidence. The methodology is particularly useful in functional Magnetic Resonance Imaging cluster analysis, where it provides a confidence statement on the percentage of truly activated voxels within clusters of voxels, avoiding the well-known spatial specificity paradox. We offer a user-friendly tool to estimate the percentage of true discoveries for each cluster while controlling the family-wise error rate for multiple testing and taking into account that the cluster was chosen in a data-driven way. The method adapts to the spatial correlation structure that characterizes functional Magnetic Resonance Imaging data, gaining power over parametric approaches. Show less
Generalized linear models are often misspecified because of overdispersion, heteroscedasticity and ignored nuisance variables. Existing quasi-likelihood methods for testing in misspecified models... Show moreGeneralized linear models are often misspecified because of overdispersion, heteroscedasticity and ignored nuisance variables. Existing quasi-likelihood methods for testing in misspecified models often do not provide satisfactory type I error rate control. We provide a novel semiparametric test, based on sign flipping individual score contributions. The parameter tested is allowed to be multi-dimensional and even high dimensional. Our test is often robust against the mentioned forms of misspecification and provides better type I error control than its competitors. When nuisance parameters are estimated, our basic test becomes conservative. We show how to take nuisance estimation into account to obtain an asymptotically exact test. Our proposed test is asymptotically equivalent to its parametric counterpart. Show less
The most prevalent approach to activation localization in neuroimaging is to identify brain regions as contiguous supra-threshold clusters, check their significance using random field theory, and... Show moreThe most prevalent approach to activation localization in neuroimaging is to identify brain regions as contiguous supra-threshold clusters, check their significance using random field theory, and correct for the multiple clusters being tested. Besides recent criticism on the validity of the random field assumption, a spatial specificity paradox remains: the larger the detected cluster, the less we know about the location of activation within that cluster. This is because cluster inference implies “there exists at least one voxel with an evoked response in the cluster”, and not that “all the voxels in the cluster have an evoked response”. Inference on voxels within selected clusters is considered bad practice, due to the voxel-wise false positive rate inflation associated with this circular inference. Here, we propose a remedy to the spatial specificity paradox. By applying recent results from the multiple testing statistical literature, we are able to quantify the proportion of truly active voxels within selected clusters, an approach we call All-Resolutions Inference (ARI). If this proportion is high, the paradox vanishes. If it is low, we can further “drill down” from the cluster level to sub-regions, and even to individual voxels, in order to pinpoint the origin of the activation. In fact, ARI allows inference on the proportion of activation in all voxel sets, no matter how large or small, however these have been selected, all from the same data. We use two fMRI datasets to demonstrate the non-triviality of the spatial specificity paradox, and its resolution using ARI. We verify that the endless circularity permitted by ARI does not render its estimates overly conservative using both simulation, and a data split. Show less
Bokenkamp, R.; Brempt, R. van; Munsteren, J.C. van; Wijngaert, I. van den; Hoogt, R. de; Finos, L.; ... ; DeRuiter, M.C. 2014
OBJECTIVE In the past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. In this pathway, glycogen synthase kinase-3β... Show moreOBJECTIVE In the past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. In this pathway, glycogen synthase kinase-3β (GSK3β) down-regulates transduction of the canonical Wnt signal by promoting degradation of β-catenin. In this study we wanted to further investigate the role of Gsk3β in cartilage maintenance. DESIGN Therefore, we have treated chondrocytes ex vivo and in vivo with GIN, a selective GSK3β inhibitor. RESULTS In E17.5 fetal mouse metatarsals, GIN treatment resulted in loss of expression of cartilage markers and decreased chondrocyte proliferation from day 1 onward. Late (3 days) effects of GIN included cartilage matrix degradation and increased apoptosis. Prolonged (7 days) GIN treatment resulted in resorption of the metatarsal. These changes were confirmed by microarray analysis showing a decrease in expression of typical chondrocyte markers and induction of expression of proteinases involved in cartilage matrix degradation. An intra-articular injection of GIN in rat knee joints induced nuclear accumulation of β-catenin in chondrocytes 72 h later. Three intra-articular GIN injections with a 2 days interval were associated with surface fibrillation, a decrease in glycosaminoglycan expression and chondrocyte hypocellularity 6 weeks later. CONCLUSIONS These results suggest that, by down-regulating β-catenin, Gsk3β preserves the chondrocytic phenotype, and is involved in maintenance of the cartilage extracellular matrix. Short term β-catenin up-regulation in cartilage secondary to Gsk3β inhibition may be sufficient to induce osteoarthritis-like features in vivo. Show less
Miclea, R.L.; Siebelt, M.; Finos, L.; Goeman, J.J.; Lowik, C.W.G.M.; Oostdijk, W.; ... ; Karperien, M. 2011
Owing to our lack of understanding of the factors that constitute protective immunity during natural infection with Mycobacterium tuberculosis (Mtb), there is an urgent need to identify host... Show moreOwing to our lack of understanding of the factors that constitute protective immunity during natural infection with Mycobacterium tuberculosis (Mtb), there is an urgent need to identify host biomarkers that predict long-term outcome of infection in the absence of therapy. Moreover, the identification of host biomarkers that predict (in)adequate response to tuberculosis (TB) treatment would similarly be a major step forward. To identify/monitor multi-component host biomarker signatures at the transcriptomic level in large human cohort studies, we have developed and validated a dual-color reverse-transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) method, permitting rapid and accurate expression profiling of as many as 60-80 transcripts in a single reaction. dcRT-MLPA is sensitive, highly reproducible, high-throughput, has an extensive dynamic range and is as quantitative as QPCR. We have used dcRT-MLPA to characterize the human immune response to Mtb in several cohort studies in two genetically and geographically diverse populations. A biomarker signature was identified that is strongly associated with active TB disease, and was profoundly distinct from that associated with treated TB disease, latent infection or uninfected controls, demonstrating the discriminating power of our biomarker signature. Identified biomarkers included apoptosis-related genes and T-cell/B-cell markers, suggesting important contributions of adaptive immunity to TB pathogenesis.Genes and Immunity advance online publication, 29 September 2011; doi:10.1038/gene.2011.64. Show less
Goeman, J.J.; Houwelingen, H.C. van; Finos, L. 2011
Testing a low-dimensional null hypothesis against a high-dimensional alternative in a generalized linear model may lead to a test statistic that is a quadratic form in the residuals under the null... Show moreTesting a low-dimensional null hypothesis against a high-dimensional alternative in a generalized linear model may lead to a test statistic that is a quadratic form in the residuals under the null model. Using asymptotic arguments, we show that the distribution of such a test statistic can be approximated by a ratio of quadratic forms in normal variables, for which algorithms are readily available. For generalized linear models, the asymptotic distribution shows good control of type I error for moderate to small samples, even when the number of covariates in the model far exceeds the sample size. Show less
