Proportional thresholding in resting-state fMRI functional connectivity networks and consequences for patient-control connectome studies: Issues and recommendations.
Graph theoretical analysis has become an important tool in the examination of brain dysconnectivity in neurological and psychiatric brain disorders. A common analysis step in the construction of the functional graph or network involves "thresholding" of the connectivity matrix, selecting the set of edges that together form the graph on which network organization is evaluated. To avoid systematic differences in absolute number of edges, studies have argued against the use of an "absolute threshold" in case-control studies and have proposed the use of "proportional thresholding" instead, in which a pre-defined number of strongest connections are selected as network edges, ensuring equal network density across datasets. Here, we systematically studied the effect of proportional thresholding on the construction of functional matrices and subsequent graph analysis in patient-control functional connectome studies. In a few simple experiments we show that differences in overall strength of functional connectivity (FC) - as often observed between patients and controls - can have predictable consequences for between-group differences in network organization. In individual networks with lower overall FC the proportional thresholding algorithm has to select more edges based on lower correlations, which have (on average) a higher probability of being spurious, and thus introduces a higher degree of randomness in the resulting network. We show across both empirical and artificial patient-control datasets that lower levels of overall FC in either the patient or control group will most often lead to differences in network efficiency and clustering, suggesting that differences in FC across subjects will be artificially inflated or translated into differences in network organization. Based on the presented case-control findings we inform about the caveats of proportional thresholding in patient-control studies in which groups show a between-group difference in overall FC. We make recommendations on how to examine, report and to take into account overall FC effects in future patient-control functional connectome studies.
Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100 PO Box 85500, Room: A01.126, Utrecht, GA 3508, The Netherlands. Electronic address: M.P.vandenheuvel@umcutrecht.nl.
Martijn P
MP
van den Heuvel
Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100 PO Box 85500, Room: A01.126, Utrecht, GA 3508, The Netherlands.
Siemon C
SC
de Lange
Melbourne Neuropsychiatry Centre & Melbourne School of Engineering, The University of Melbourne, Australia.
Andrew
A
Zalesky
Melbourne Neuropsychiatry Centre & Melbourne School of Engineering, The University of Melbourne, Australia.
Caio
C
Seguin
Dept of Electrical and Computer Engineering, Clinical Imaging Research Center, Singapore Institute for Neurotechnology, Memory Network Program, National University of Singapore, Singapore.
B T Thomas
BTT
Yeo
Brain Center Rudolf Magnus, Department of Neurology, University Medical Center Utrecht, The Netherlands.
Ruben
R
Schmidt
D000465:Algorithms; D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging / Q000503:physiopathology; D000067877:Autism Spectrum Disorder / Q000000981:diagnostic imaging / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging* / Q000503:physiopathology; D016022:Case-Control Studies; D063132:Connectome / Q000379:methods*; D004569:Electroencephalography; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D001523:Mental Disorders / Q000000981:diagnostic imaging* / Q000503:physiopathology; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000503:physiopathology; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000503:physiopathology; D012815:Signal Processing, Computer-Assisted