The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder

Li, Danyang; Olsson, Nora Choque; Jiao, Hong; Norgren, Nina; Jönsson, Ulf; Bölte, Sven; Tammimies, Kristiina

doi:10.1038/s41525-020-00152-x

Cited by 14 publications

(14 citation statements)

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“…The main problems of multiple distortions under the term "ASD" are also existent. Li et al, [59] show the usage of PRS combined with selected training sets for ASD individuals. This seems to be an interesting approach for PRS and real usage.…”

Section: Discussionmentioning

confidence: 99%

Cost-Effectiveness of Autism Diagnostic Based on Genetic Testing

Rudolph-Rothfeld

Vonthein

2021

Preprint

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Background: Autism Spectrum Disorder (ASD) is a highly heritable polygenetic disorder with several degrees of handicap.Novel genetic diagnostics for Autism Spectrum Disorder promise an earlier diagnosis than psychometric diagnostics, but their cost-effectiveness is unproven.Objective: To model the clinical pathway from diagnosis to early intervention (EI) and outcome in scenarios with genetic diagnostics compared to just psychometric diagnosis that follows a current guideline (Status Quo). Methods: Early diagnosis based on genetic testing leads to more intensive and effective early intervention. Future scenarios assume genetic screening(Screening), genetic testing on request(GenADD), or genetic testing in cases with a family history of ASD(Predisposition). Simulations on Markov models using software TreeAge v. 2018 and parameters found in the literature. The time horizon reached from birth to the 15th year of life with cycle length 1 year. The models were stratified by autism severity, i.e. IQ initially below 70 or above. Effectiveness was both, dependency free life years (DFLY) gained by correct diagnosis and successful treatment, and the number of diagnosed patients that became independent after treatment. We choose the insurance view. Just direct costs for diagnostics and treatment were considered. Probabilistic sensitivity analyses (PSA) explore assumptions of different parameters, like the sensitivity of the genetic test, using the precisions stated in the literature or possible future developments. Results: Status Quo is the most cost-effective scenario with the current parameter values. The other scenarios follow in the order of Predisposition, GenADD, and Screening. All scenarios with genetic tests have a higher number of detection than Status Quo. Intensified early intervention may be cost effective with horizon 67 years. The currently high false positive rate of genetic testing might be detrimental to that. Discussion: Low precision of published parameter estimates led to wide confidence intervals for our estimates of cost-effectiveness. Our model shows that Screening and GenADD should not be an option for inaccurate genetic tests. Once they are more accurate, the potential of early intervention may unfold.Conclusion: Further evaluations with better data need to underpin the current results.

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Section: Discussionmentioning

confidence: 99%

Cost-Effectiveness of Autism Diagnostic Based on Genetic Testing

Rudolph-Rothfeld

Vonthein

2021

Preprint

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“…Social skills group training (SSGT) is a behavioral intervention widely applied in ASD to ameliorate social communication difficulties, with varied responses depending on factors such as age and sex [20]. In addition, our group demonstrated that both rare CNVs and common variant PRS could affect individual intervention outcomes in a randomized controlled trial evaluating the SSGT KONTAKT® [21,22]. Seeking to examine further the role of rare variants on individual outcomes of SSGT and standard care, we performed exome sequencing in the participants and leveraged all level genetic data and clinical information from the KONTAKT® trial [20], as summarized in Figure 1.…”

Section: Introductionmentioning

confidence: 95%

“…In addition to exome sequencing, we used our earlier acquired data on clinically significant copy number variations (CNVs) and common variants polygenic risk score (PRS) for ASD [21,22]. The distribution of PRS for ASD did not differ between individuals with or without VCS/VUS from exome sequencing (P = 0.37, Supplementary Fig 4a…”

Section: Clinically Significant Variants and Phenotype Characteristicsmentioning

confidence: 99%

“…We also tested the interaction of PRS for ASD from our previous study [22] and VCS/VUS in the linear model. Outcomes at post-intervention and follow-up were measured by SRS changes at two time points compared to pre-intervention.…”

Section: Association Between Carrier Status and Srs Scorementioning

confidence: 99%

“…The number of synaptic genes captured by two kinds of rare variants was added and divided by the number of brain-expressed genes with rare variants in each individual. Next, we generated GSSyT for the common variants (GSSyTc) acquired from the previous study [22]. The calculation of GSSyTc was based on set-based polygenic risk score (PRS) using a new feature of PRSice named PRSet (https://www.prsice.info/quick_start_prset/).…”

Section: Genetic Score For Synaptic Transmission (Gssyt)mentioning

confidence: 99%

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Rare variants in the outcome of social skills group training for autism

Olsson

Becker

et al. 2021

Preprint

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Background Exome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify a molecular diagnosis of ASD and genetic modulators of intervention outcomes following social skills group training (SSGT) or standard care. Methods Within a randomized controlled trial of SSGT, we performed exome sequencing to prioritize variants of clinical significance (VCSs), variants of uncertain significance (VUSs) and generated a pilot scheme to calculate genetic scores representing the genetic load of rare and common variants in the synaptic transmission pathway (GSSyTr and GSSyTc). The association with the primary outcomes (parent-reported autistic traits, Social Responsiveness Scale) was computed using a mixed linear model. Behavioral and genetic features were combined in a machine learning (ML) model to predict the individual response within the cohort. Results In total, 4.4% (n = 9) and 11.3% (n = 23) of the cohort carried VCSs and VUSs, respectively. Compared to non-carriers, individuals with VCS or VUS together tended to have limited improvements of the interventions (β = 9.22; CI (-0.25, 18.70); P = 0.057) and improved significantly less from standard care (β = 9.35; CI (0.70, 18.00); P = 0.036), but not from SSGT (β = -2.50; CI (-13.34, 8.35); P = 0.65). In addition, both GSSyTr and GSSyTc were associated with differential outcomes in standard care and SSGT groups. Our ML model showed the importance of rare variants for outcome prediction. Conclusions Autistic individuals with likely pathogenic rare variants identified by exome sequencing might benefit less from the standard care. SSGT could therefore be of heightened importance for this subgroup. Further studies are needed to understand genetic predisposition to intervention outcomes.

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Rare variants in the outcome of social skills group training for autism

Olsson

Becker

et al. 2021

Autism Research

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Exome sequencing has been proposed as the first-tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify molecular diagnoses and genetic modifiers of intervention outcomes of social skills group training (SSGT) or standard care. We prioritized variants of clinical significance (VCS), variants of uncertain significance (VUS) and generated a pilot scheme to calculate genetic scores of rare and common variants in ASD-related gene pathways. Mixed linear models were used to test the association between the carrier status of VCS/VUS or the genetic scores with intervention outcomes measured by the social responsiveness scale. Additionally, we combined behavioral and genetic features using a machine learning (ML) model to predict the individual response. We showed a rate of 4.4% and 11.3% of VCS and VUS in the cohort, respectively. Individuals with VCS or VUS had improved significantly less after standard care than non-carriers at post-intervention (β = 9.35; p = 0.036), while no such association was observed for SSGT (β = À2.50; p = 0.65). Higher rare variant genetic scores for synaptic transmission and regulation of transcription from RNA polymerase II were separately associated with less beneficial (β = 8.30, p = 0.0044) or more beneficial (β = À6.79, p = 0.014) effects after SSGT compared with standard care at follow-up, respectively. Our ML model showed the importance of rare variants for outcome prediction. Further studies are needed to understand genetic predisposition to intervention outcomes in ASD. Lay SummarySocial skills group training is one of the most common behavior interventions aiming at autistic children and adolescents, but the outcome varies between Sven Bölte and Kristiina Tammimies contributed equally to this study.

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The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder

Cited by 14 publications

References 64 publications

Cost-Effectiveness of Autism Diagnostic Based on Genetic Testing

Cost-Effectiveness of Autism Diagnostic Based on Genetic Testing

Rare variants in the outcome of social skills group training for autism

Rare variants in the outcome of social skills group training for autism

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