Small effect size leads to reproducibility failure in resting-state fMRI studies

Jia, X.-Z.; Zhao, N.; Barton, B.; Burciu, R.; Carriere, N.; Cerasa, A.; Chen, B.-Y.; Chen, J.; Coombes, S.; Defebvre, L.; Delmaire, C.; Dujardin, K.; Esposito, F.; Fan, G.-G.; Federica, D. N.; Feng, Y.-X.; Fling, B. W.; Garg, S.; Gilat, M.; Gorges, M.; Ho, S.-L.; Horak, F. B.; Hu, X.; Hu, X.-F.; Huang, B.; Huang, P.-Y.; Jia, Z.-J.; Jones, C.; Kassubek, J.; Krajcovicova, L.; Kurani, A.; Li, J.; Li, Q.; Liu, A.-P.; Liu, B.; Liu, H.; Liu, W.-G.; Lopes, R.; Lou, Y.-T.; Luo, W.; Madhyastha, T.; Mao, N.-N.; McAlonan, G.; McKeown, M. J.; Pang, S. Y.; Quattrone, A.; Rektorova, I.; Sarica, A.; Shang, H

doi:10.1101/285171

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bioRxiv · 10.1101/285171

Small effect size leads to reproducibility failure in resting-state fMRI studies

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Abstract

Thousands of papers using resting-state functional magnetic resonance imaging (RS-fMRI) have been published on brain disorders. Results in each paper may have survived correction for multiple comparison. However, since there have been no robust results from large scale meta-analysis, we do not know how many of published results are truly positives. The present meta-analytic work included 60 original studies, with 57 studies (4 datasets, 2266 participants) that used a between-group design and 3 studies (1 dataset, 107 participants) that employed a within-group design. To evaluate the effect size of brain disorders, a very large neuroimaging dataset ranging from neurological to psychiatric isorders together with healthy individuals have been analyzed. Parkinsons disease off levodopa (PD-off) included 687 participants from 15 studies. PD on levodopa (PD-on) included 261 participants from 9 studies. Autism spectrum disorder (ASD) included 958 participants from 27 studies. The meta-analyses of a metric named amplitude of low frequency fluctuation (ALFF) showed that the effect size (Hedges g) was 0.19 - 0.39 for the 4 datasets using between-group design and 0.46 for the dataset using within-group design. The effect size of PD-off, PD-on and ASD were 0.23, 0.39, and 0.19, respectively. Using the meta-analysis results as the robust results, the between-group design results of each study showed high false negative rates (median 99%), high false discovery rates (median 86%), and low accuracy (median 1%), regardless of whether stringent or liberal multiple comparison correction was used. The findings were similar for 4 RS-fMRI metrics including ALFF, regional homogeneity, and degree centrality, as well as for another widely used RS-fMRI metric namely seed-based functional connectivity. These observations suggest that multiple comparison correction does not control for false discoveries across multiple studies when the effect sizes are relatively small. Meta-analysis on un-thresholded t-maps is critical for the recovery of ground truth. We recommend that to achieve high reproducibility through meta-analysis, the neuroimaging research field should share raw data or, at minimum, provide un-thresholded statistical images.

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Jia, X.-Z., Zhao, N., Barton, B., Burciu, R., Carriere, N., Cerasa, A., Chen, B.-Y., Chen, J., Coombes, S., Defebvre, L., Delmaire, C., Dujardin, K., Esposito, F., Fan, G.-G., Federica, D. N., Feng, Y.-X., Fling, B. W., Garg, S., Gilat, M., Gorges, M., Ho, S.-L., Horak, F. B., Hu, X., Hu, X.-F., Huang, B., Huang, P.-Y., Jia, Z.-J., Jones, C., Kassubek, J., Krajcovicova, L., Kurani, A., Li, J., Li, Q., Liu, A.-P., Liu, B., Liu, H., Liu, W.-G., Lopes, R., Lou, Y.-T., Luo, W., Madhyastha, T., Mao, N.-N., McAlonan, G., McKeown, M. J., Pang, S. Y., Quattrone, A., Rektorova, I., Sarica, A., Shang, H. 2018-03-20. Small effect size leads to reproducibility failure in resting-state fMRI studies. https://doi.org/10.1101/285171

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