Cited by 107Functional Brain Connectivity StudiesMental Health Research TopicsAttention Deficit Hyperactivity Disorder

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Organizing Heterogeneous Samples Using Community Detection of GIMME-Derived Resting State Functional Networks

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Abstract

Clinical investigations of many neuropsychiatric disorders rely on the assumption that diagnostic categories and typical control samples each have within-group homogeneity. However, research using human neuroimaging has revealed that much heterogeneity exists across individuals in both clinical and control samples. This reality necessitates that researchers identify and organize the potentially varied patterns of brain physiology. We introduce an analytical approach for arriving at subgroups of individuals based entirely on their brain physiology. The method begins with Group Iterative Multiple Model Estimation (GIMME) to assess individual directed functional connectivity maps. GIMME is one of the only methods to date that can recover both the direction and presence of directed functional connectivity maps in heterogeneous data, making it an ideal place to start since it addresses the problem of heterogeneity. Individuals are then grouped based on similarities in their connectivity patterns using a modularity approach for community detection. Monte Carlo simulations demonstrate that using GIMME in combination with the modularity algorithm works exceptionally well--on average over 97% of simulated individuals are placed in the accurate subgroup with no prior information on functional architecture or group identity. Having demonstrated reliability, we examine resting-state data of fronto-parietal regions drawn from a sample (N = 80) of typically developing and attention-deficit/hyperactivity disorder (ADHD) -diagnosed children. Here, we find 5 subgroups. Two subgroups were predominantly comprised of ADHD, suggesting that more than one biological marker exists that can be used to identify children with ADHD based from their brain physiology. Empirical evidence presented here supports notions that heterogeneity exists in brain physiology within ADHD and control samples. This type of information gained from the approach presented here can assist in better characterizing patients in terms of outcomes, optimal treatment strategies, potential gene-environment interactions, and the use of biological phenomenon to assist with mental health.

Overview

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TL;DR

The paper introduces a data-driven method that combines GIMME-derived individual directed functional connectivity maps with Newman modularity community detection to identify subgroups of individuals based on brain physiology alone. In simulations it recovered subgroups with high accuracy, and in resting-state fMRI from 80 children it found five subgroups, with two predominantly ADHD, supporting heterogeneity within ADHD and control samples.

Key findings

  • In Monte Carlo simulations (100 individuals, 10 brain regions), GIMME recovered group-level connections for all 100 datasets and, on average, 99.73% (SD = 0.09%, range = 95–100%) of individual connections accurately in presence and direction.
  • Community detection placed on average 97.23% (SD = 1.87%, range = 92–100%) of simulated individuals into the correct subgroup without prior group information.
  • In the empirical sample of 80 children (32 ADHD, 48 typically developing controls), the method found 5 subgroups; ADHD and control participants were distributed across subgroups at greater than chance levels (χ² = 12.32, df = 4, p = .015), while sex distribution did not differ from chance (χ² = 3.65, df = 4, p = .456).
  • Comparing ADHD and control as homogeneous diagnostic groups revealed no significant differences in path weights, but subgroup analyses showed different connectivity patterns: e.g., subgroup B had weaker L dlPFC→L IPS connectivity, while subgroup D had stronger L dlPFC→L IPS connectivity and decreased L FC→R FC connectivity.

Methods

  • Resting-state fMRI data were analyzed from simulated datasets and an empirical sample of 80 children aged 7–12; 11 fronto-parietal ROIs were selected, and individual directed functional connectivity maps were estimated with GIMME within a unified structural equation modeling framework.
  • Each individual’s contemporaneous connection weights were vectorized, correlated with every other individual’s vector to form a similarity matrix, binarized at a data-driven threshold, and submitted to Newman’s modularity community detection algorithm.
  • Threshold selection used stability of the modularity index Q across 100 runs and a reachability criterion; robustness of community structure was tested via perturbation and variation of information, and subgroup connection weights were compared using ANOVA with FDR correction at alpha = 0.05.

Limitations

  • The paper states that community detection algorithms have proliferated without formal comparison, that Newman’s algorithm is widely used but likely not optimal for all situations, and that many fMRI community detection approaches were tested on larger adjacency matrices and may not be optimal for smaller matrices where nodes are participants.
  • The paper also states that similarity-matrix construction could vary with preprocessing choices such as global signal regression, that lagged paths could alternatively be used, and that individual-level paths were omitted because their heterogeneity produced groups too small to be useful; future work is needed for non-normally distributed data.
  • Evident from the text: the empirical findings come from a modest cross-sectional sample (N = 80) with no independent replication or outcome/treatment validation, and the “protective” versus “risk” subgroup interpretations are proposed as hypotheses rather than confirmed clinical predictions.

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Registry

Crossref · 10.1371/journal.pone.0091322

Cites

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Statistics

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Figures

Figure 1 Schema of analytic process. Analysis were conducted using the following steps: a) obtain timeseries of functional MRI observations from regions of interest; b) arrive at directed functional connectivity maps for each individual using GIMME; c) correlate each individual's vector of connection weights with every other individual's vector for a similarity matrix; d) apply Newman's modularity maximization algorithm to similarity matrix to arrive at subgroups of individuals based on similar brain connectivity patterns.
Figure 1 Schema of analytic process. Analysis were conducted using the following steps: a) obtain timeseries of functional MRI observations from regions of interest; b) arrive at directed functional connectivity maps for each individual using GIMME; c) correlate each individual's vector of connection weights with every other individual's vector for a similarity matrix; d) apply Newman's modularity maximization algorithm to similarity matrix to arrive at subgroups of individuals based on similar brain connectivity patterns.CC BY · PubMed Central
Figure 2 Instability in Q index. This is taken across 100 iterations at each threshold from 0.0 to 1.0 at .01 increments.
Figure 2 Instability in Q index. This is taken across 100 iterations at each threshold from 0.0 to 1.0 at .01 increments.CC BY · PubMed Central
Figure 3 Q index and reachability across thresholds. Q values across all thresholds (top panel); average number of individuals each individual can reach at each threshold (i.e., reachability) and visual depiction (grey, dotted lines) of approach for defining the point at which reachability begins to decrease (middle panel); Q values (bottom panel) up until drop in reachability (denoted with a red circle in the middle panel). The optimal r thresholds with maximum stability, Q index value, and reachability criteria were .60 and .56 for the simulated data example presented here (1 of 100 runs) and empirical data, respectively.
Figure 3 Q index and reachability across thresholds. Q values across all thresholds (top panel); average number of individuals each individual can reach at each threshold (i.e., reachability) and visual depiction (grey, dotted lines) of approach for defining the point at which reachability begins to decrease (middle panel); Q values (bottom panel) up until drop in reachability (denoted with a red circle in the middle panel). The optimal r thresholds with maximum stability, Q index value, and reachability criteria were .60 and .56 for the simulated data example presented here (1 of 100 runs) and empirical data, respectively.CC BY · PubMed Central
Figure 4 Patterns of effects used to simulate data and results.
Figure 4 Patterns of effects used to simulate data and results.CC BY · PubMed Central
Figure 5 Regions and results from empirical sample. Red lines indicate the subgroup had higher connection values than the average of the other subgroups; blue lines indicate the subgroup had lower connection values than the average of the other subgroups; gray paths indicate the connection values were similar to the average of other subgroups. Abbreviations: “dlPFC” = dorsolateral prefrontal cortex; “FC” = frontal cortex; “IPS” = intraperietal sulcus; “IPL” = inferior parietal lobule; “R” preceding these ROI names and abbreviations denotes right and “L” denotes left.
Figure 5 Regions and results from empirical sample. Red lines indicate the subgroup had higher connection values than the average of the other subgroups; blue lines indicate the subgroup had lower connection values than the average of the other subgroups; gray paths indicate the connection values were similar to the average of other subgroups. Abbreviations: “dlPFC” = dorsolateral prefrontal cortex; “FC” = frontal cortex; “IPS” = intraperietal sulcus; “IPL” = inferior parietal lobule; “R” preceding these ROI names and abbreviations denotes right and “L” denotes left.CC BY · PubMed Central
Figure 6 Variation of information (VI) in simulated and empirical data across varying degrees of perturbation. Red triangles indicate VI values obtained from random perturbations; black squares correspond to VI values obtained on the original matrices.
Figure 6 Variation of information (VI) in simulated and empirical data across varying degrees of perturbation. Red triangles indicate VI values obtained from random perturbations; black squares correspond to VI values obtained on the original matrices.CC BY · PubMed Central
Figure 7 Subgroup make-up: Controls and ADHD.
Figure 7 Subgroup make-up: Controls and ADHD.CC BY · PubMed Central

Verification

Claims the paper makes

38 Not checked yet · 36 Own result · 31 Own interpretation · 10 No basis given · 1 Own method

Verify all 57 references — free account

Show all 61 claims

  • It may state two separate claims as one. 30
  • The quote only partly states this claim. 1
  • Probably not a substantial claim. 30
55 of 55
  • The authors state this as an assumption.

    Clinical investigations of many neuropsychiatric disorders rely on the assumption that diagnostic categories and typical control samples each have within-group homogeneity.

    “Clinical investigations of many neuropsychiatric disorders rely on the assumption that diagnostic categories and typical control samples each have within-group homogeneity.”
  • The paper relies on this without support.

    Studies examining the etiology of any given disorder typically ignore the potential heterogeneity that exists within current symptom-based classifications.

    “While it is largely agreed that the above possibility exists, studies examining the etiology of any given disorder typically ignore the potential heterogeneity that exists within current symptom-based classifications.”
  • The paper relies on this without support.

    Analyses are conducted as though both the diagnostic group and the comparison control group represent two homogeneous populations.

    “In accordance with the current standard, analyses are conducted as though both the diagnostic group and the comparison control group represent two homogeneous populations.”
  • The paper relies on this without support.

    rs-fcMRI is developmentally and contextually more variable than brain structural measures.

    “A benefit of rs-fcMRI is that it is developmentally and contextually more variable than brain structural measures, making it a highly attractive place to start towards the goal of identifying subgroups of individuals based on similar brain processes.”
  • The paper relies on this without support.

    rs-fcMRI can be administered across any age range, species, or cognitive ability.

    “Furthermore, it can be administered at across any age range, species, or cognitive ability.”
  • The paper relies on this without support.

    Prior rs-fcMRI analyses have revealed ongoing information processing between spatially disparate regions of the brain even during rest, and differences in these processes relate to cognitive performance and psychiatric disorders.

    “Prior rs-fcMRI analyses have revealed that there is ongoing information processing between spatially disparate regions of the brain even during rest, and differences in these observed processes relate to cognitive performance as well as psychiatric disorders.”
  • The paper relies on this without support.

    Sample-level connections will have normally distributed estimates across individuals.

    “An added benefit is that sample-level connections will have normally distributed estimates across individuals, making it appropriate for the correlation analysis to follow.”
  • The paper relies on this without support.

    Researchers commonly select thresholds that provide the highest modularity index.

    “Researchers commonly select thresholds (or solutions) that provide the highest modularity index.”
  • The paper relies on this without support.

    The ADHD and TDC diagnostic categories are valid and meaningful groupings for the analyses.

    “we placed and analyzed the individuals into groups based on their diagnostic status.”
  • The paper relies on this without support.

    The sample of children is representative of the broader ADHD and typically developing populations to which the findings are generalized.

    “These findings demonstrate that heterogeneity exists within both control and ADHD populations”
10 of 10

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Citations

Cites

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Research works printed but not linked: 1

  1. FR Volkmar, 2004, Autism and pervasive mental disorders, Journal of Child Psychology and Psychiatry, 45: 135, 170

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Metadata

Authors
Gates, K. M., Molenaar, P. C. M., Iyer, S. P., Nigg, J. T., & Fair, D. A.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Pennsylvania State University (US)
  • Oregon Health & Science University (US)
Corresponding author
Gates, Kathleen M.
Venue
PLoS ONE
Published
2014-03-18
Volume
9
Issue
3
Pages
e91322
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2047219509
Cited by
107
References
58
Citations by year
2026: 4 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 12 · 2021: 6 · 2020: 14 · 2019: 17 · 2018: 9 · 2017: 14 · 2016: 9 · 2015: 6 · 2014: 3
FWCI
5.95
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UNC Libraries
Funders
  • National Science Foundation (1157220)
  • National Institutes of Health (1157220, K99-R00, K99/R00 MH091238, MH091238)
  • Oregon Clinical and Translational Research Institute
  • National Institute of Mental Health (K99/R00 MH091238, K99MH091238, R01MH115357, R01 MH86654, R00MH091238, R01MH096773, R01MH086654)
  • National Institute of Biomedical Imaging and Bioengineering (R21EB015573)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Mental Health Research Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Keywords
group iterative multiple model estimation, directed functional connectivity, resting-state networks, community detection, modularity, patient heterogeneity, subgroup identification, attention deficit hyperactivity disorder, children, frontoparietal connectivity, biomarkers, neuropsychiatric disorders
MeSH terms
Attention Deficit Disorder with Hyperactivity, Brain Mapping, Child, Computer Simulation, Female, Frontal Lobe, Humans, Magnetic Resonance Imaging, Male, Neural Pathways, Parietal Lobe, Residence Characteristics, Models, Statistical, Biomarkers, Case-Control Studies, Genetic Heterogeneity, Gene-Environment Interaction

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