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. 2024 May 16:15:1384134.
doi: 10.3389/fpsyt.2024.1384134. eCollection 2024.

Exome functional risk score and brain connectivity can predict social adaptability outcome of children with autism spectrum disorder in 4 years' follow up

Tingting Luo #  1 , Manxue Zhang #  1 , Sixun Li  1 , Mingjing Situ  1 , Pei Liu  1 , Meiwen Wang  1 , Yujie Tao  1 , Shengnan Zhao  1 , Zhuo Wang  1 , Yanping Yang  1 , Yi Huang  1
Affiliations

Exome functional risk score and brain connectivity can predict social adaptability outcome of children with autism spectrum disorder in 4 years' follow up

Tingting Luo et al. Front Psychiatry. .

Abstract

Introduction: Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder emerging in early childhood, with heterogeneous clinical outcomes across individuals. This study aims to recognize neuroimaging genetic factors associated with outcomes of ASD after a 4-year follow-up.

Methods: A total of 104 ASD children were included in this study; they underwent clinical assessments, MRI data acquisition, and the whole exome sequencing (WES). Exome functional risk score (EFRS) was calculated based on WES; and two modalities of brain connectivity were constructed based on MRI data, that is functional connectivity (FC) for functional MRI (fMRI), and individual differential structural covariance network (IDSCN) for structural MRI (sMRI), to explore the neuroimaging genetic biomarker of outcomes of ASD children.

Results: Regression analysis found EFRS predicts social adaptability at the 4-year follow-up (Y = -0.013X + 9.29, p = 0.003). We identified 19 pairs of FC associated with autism symptoms severity at follow-up, 10 pairs of FC and 4 pairs of IDSCN associated with social adaptability at follow-up, and 10 pairs of FC associated with ASD EFRS by support vector regression (SVR). Related brain regions with prognostic predictive effects are mainly distributed in superior frontal gyrus, occipital cortex, temporal cortex, parietal cortex, paracentral lobule, pallidum, and amygdala for FC, and temporal cortex, thalamus, and hippocampus for IDSCN. Mediation model showed that ASD EFRS affects the social communication of ASD children through the mediation of FC between left middle occipital gyrus and left pallidum (RMSEA=0.126, CMIN=80.66, DF=42, p< 0.001, CFI=0.867, AIC=152).

Discussion: Our findings underscore that both EFRS and brain connectivity can predict social adaptability, and that brain connectivity serving as mediator in the relationship of EFRS and behaviors of ASD, suggesting the intervention targets in the future clinical application.

Keywords: autism spectrum disorder (ASD); brain connectivity; exome functional risk score (EFRS); functional connectivity (FC); individual differential structural covariance network (IDSCN); outcome; prediction; social adaptability.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flowchart for the participant recruitment. ASD−, ASD with optimal outcome; ASD+, ASD with poor outcome; WES, whole exome sequencing.
Figure 2
Figure 2
Relationships between EFRS and outcomes of ASD. (A) Simple linear regression analysis shows EFRS could predict the social adaptability of ASD children (Y= -0.013*X+ 9.29, p = 0.003); (B) Simple logistic regression analysis shows EFRS could not predict the outcome grouping (Y= -0.0008*X+ 0.95, p = 0.914). The solid line shows the distribution trend of the values; The dashed line represents the 95% confidence interval. EFRS, exome functional risk scores; S-M, the infants-junior middle school students’ social-life abilities scale; ASD-, ASD with optimal outcome; ASD+, ASD with poor outcome.
Figure 3
Figure 3
Brain connectivity with predictive effects. (A) SVR model for ADOS total scores results based on FC (fMRI); the left displays the 19 pairs of congruent brain regions; the right shows circle diagram of the identified congruent brain regions, red represents positive weight and blue represents negative weight; (B) SVR model for social adaptability results based on FC (fMRI), 10 pairs of congruent brain regions displayed; (C) SVR model for social adaptability results based on IDSCN (sMRI), 4 pairs of congruent brain regions displayed. SVR, support Vector Regression; ADOS, autism diagnostic observation schedule; FC, functional connectivity; IDSCN, individual differential structural covariance network; fMRI, functional MRI; sMRI, structural MRI.
Figure 4
Figure 4
Multiple logistic regression analysis results of outcomes of ASD children. (A) Multiple logistic regression results of the symptoms severity (outcome grouping). There is no significant predictive effect of the 19 pairs of FC nor EFRS on symptoms severity of ASD children at 4-year follow-up. (B) Multiple logistic regression results of social adaptability (OSO). Risk factors for social adaptability include 3 pairs of IDSCN that is bilateral thalamus, left thalamus (THA.L) to right hippocampus (HIP.R), and left angular gyrus (ANG.L) to left fusiform gyrus (FFG.L), and 3 pairs of FC, that is right Heschl gyrus (HES.R) to right middle temporal gyrus (MTG.R), left angular gyrus (ANG.L) to left paracentral lobule (PCL.L), and left angular gyrus (ANG.L) to right inferior occipital gyrus (IOG.R); protective factors for social adaptability include 4 pairs of FC, that is left superior temporal gyrus (STG.L) to right amygdala (AMYG.R), left paracentral lobule (PCL.L) to medial orbital of left superior frontal gyrus (ORBsupmed.L), left precuneus (PCUN.L) to left angular gyrus (ANG,L), and left superior parietal gyrus (SPG.L) to right inferior occipital gyrus (IOG.R). (C) Multiple logistic regression results of social adaptability based on FC associated with EFRS. FC of left middle occipital gyrus (MOG.L) and right paracentral lobule (PCL.R) is a risk factor for outcomes (OR=7.08, 95%CI=5.32 - 12.03). Red represents OR > 1, which is a risk factor for poor outcome; Green represents OR< 1, which is a protective factor for good outcome; Black represents no predictive value; Cut-off values represent OR values much larger than 5. The results are adjusted by post hoc Bonferroni correction, and significant p-value is 0.05. IDSCN, individual differential structural covariance network; FC, functional connectivity; EFRS, exome functional risk score; ROI, region of interest.
Figure 5
Figure 5
Mediation model of EFRS, brain connectivity and behaviors of children with ASD. EFRS has a direct effect on the FC of MOG.L and PAL.L (r - -0.47, p< 0.001); FC of MOG.L and PAL.L has a direct effect on communication symptom (r - -0.36, p = 0.009); EFRS has no direct effect on the communication (r = -0.10, p = 0.462), but an indirect effect (r = 0.17, p=0.03), through the mediation of FC of MOG.L and PAL.L (CMIN = 80.66, DF = 42, p< 0.001, CFI = 0.867, AIC = 152). The black solid line indicates direct effect; the black dashed line indicates the path without significance; the green solid line indicates indirect effect. r is the path weight; EFRS, exome functional risk score; MOG.L- PAL.L, functional connectivity between left middle occipital gyrus and left pallidum; ADI-R communication: communication subscale of the autism diagnostic interview-revised (ADI-R).
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Program of Chengdu Science and Technology (Grant number: 2022-YF09-00010-SN) and the Medical and Industrial Integration Project of Chengdu City (Grant number: HXDZ22014).
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