Spatially-enhanced clusterwise inference for testing and localizing intermodal correspondence.

With the increasing availability of neuroimaging data from multiple modalities-each providing a different lens through which to study brain structure or function-new techniques for comparing, integrating, and interpreting information within and across modalities have emerged. Recent developments include hypothesis tests of associations between neuroimaging modalities, which can be used to determine the statistical significance of intermodal associations either throughout the entire brain or within anatomical subregions or functional networks. While these methods provide a crucial foundation for inference on intermodal relationships, they cannot be used to answer questions about where in the brain these associations are most pronounced. In this paper, we introduce a new method, called CLEAN-R, that can be used both to test intermodal correspondence throughout the brain and also to localize this correspondence. Our method involves first adjusting for the underlying spatial autocorrelation structure within each modality before aggregating information within small clusters to construct a map of enhanced test statistics. Using structural and functional magnetic resonance imaging data from a subsample of children and adolescents from the Philadelphia Neurodevelopmental Cohort, we conduct simulations and data analyses where we illustrate the high statistical power and nominal type I error levels of our method. By constructing an interpretable map of group-level correspondence using spatially-enhanced test statistics, our method offers insights beyond those provided by earlier methods.

Bayes estimate of primary threshold in clusterwise functional magnetic resonance imaging inferences.

Clusterwise statistical inference is the most widely used technique for functional magnetic resonance imaging (fMRI) data analyses. Clusterwise statistical inference consists of two steps: (i) primary thresholding that excludes less significant voxels by a prespecified cut-off (eg, p<.001 ); and (ii) clusterwise thresholding that controls the familywise error rate caused by clusters consisting of false positive suprathreshold voxels. The selection of the primary threshold is critical because it determines both statistical power and false discovery rate (FDR). However, in most existing statistical packages, the primary threshold is selected based on prior knowledge (eg, p<.001 ) without taking into account the information in the data. In this article, we propose a data-driven approach to algorithmically select the optimal primary threshold based on an empirical Bayes framework. We evaluate the proposed model using extensive simulation studies and real fMRI data. In the simulation, we show that our method can effectively increase statistical power by 20% to over 100% while effectively controlling the FDR. We then investigate the brain response to the dose-effect of chlorpromazine in patients with schizophrenia by analyzing fMRI scans and generate consistent results.

Spatial-extent inference for testing variance components in reliability and heritability studies.

Clusterwise inference is a popular approach in neuroimaging to increase sensitivity, but most existing methods are currently restricted to the General Linear Model (GLM) for testing mean parameters. Statistical methods for testing variance components, which are critical in neuroimaging studies that involve estimation of narrow-sense heritability or test-retest reliability, are underdeveloped due to methodological and computational challenges, which would potentially lead to low power. We propose a fast and powerful test for variance components called CLEAN-V (CLEAN for testing Variance components). CLEAN-V models the global spatial dependence structure of imaging data and computes a locally powerful variance component test statistic by data-adaptively pooling neighborhood information. Correction for multiple comparisons is achieved by permutations to control family-wise error rate (FWER). Through analysis of task-fMRI data from the Human Connectome Project across five tasks and comprehensive data-driven simulations, we show that CLEAN-V outperforms existing methods in detecting test-retest reliability and narrow-sense heritability with significantly improved power, with the detected areas aligning with activation maps. The computational efficiency of CLEAN-V also speaks of its practical utility, and it is available as an R package.

Cluster success: fMRI inferences for spatial extent have acceptable false-positive rates.

In an editorial (this issue), I argued that Eklund, Nichols, and Knutsson's 'null data' reflected resting-state/default network activity that inflated their false-positive rates. Commentaries on that paper were received by Nichols, Eklund, and Knutsson (this issue), Hopfinger (this issue), and Cunningham and Koscik (this issue). In this author response, I consider these commentaries. Many issues stemming from Nichols et al. are identified including: (1) Nichols et al. did not provide convincing arguments that resting-state fMRI data reflect null data. (2) Eklund et al. presented one-sample t-test results in the main body of their paper showing that their permutation method was acceptable, while their supplementary results showed that this method produced false-positive rates that were similar to other methods. (3) Eklund et al. used the same event protocol for all the participants, which artifactually inflated the one-sample t-test false-positive rates. (4) At p < .001, using two-sample t-tests (which corrected for the flawed analysis), all the methods employed to correct for multiple comparisons had acceptable false-positive rates. (5) Eklund et al. contrasted resting-state periods, which produced many significant clusters of activity, while null data should arguably be associated with few, if any, significant activations. Eklund et al.'s entire set of results show that commonly employed methods to correct for multiple comparisons have acceptable false-positive rates. Following Hopfinger along with Cunningham and Koscik, it is also highlighted that rather than focusing on only type I error, type I error and type II error should be balanced in fMRI analysis.

Resting-state fMRI data reflects default network activity rather than null data: A defense of commonly employed methods to correct for multiple comparisons.

Analysis of functional magnetic resonance imaging (fMRI) data typically involves over one hundred thousand independent statistical tests; therefore, it is necessary to correct for multiple comparisons to control familywise error. In a recent paper, Eklund, Nichols, and Knutsson used resting-state fMRI data to evaluate commonly employed methods to correct for multiple comparisons and reported unacceptable rates of familywise error. Eklund et al.'s analysis was based on the assumption that resting-state fMRI data reflect null data; however, their 'null data' actually reflected default network activity that inflated familywise error. As such, Eklund et al.'s results provide no basis to question the validity of the thousands of published fMRI studies that have corrected for multiple comparisons or the commonly employed methods to correct for multiple comparisons.