Cognitive behavioural therapy for anxiety in children and young people on the autism spectrum: a systematic review and meta-analysis

Background Anxiety is common in youth on the autism spectrum and cognitive behavioural therapy (CBT) has been adapted to address associated symptoms. The aim of the current systematic review and meta-analysis was to examine the efficacy of CBT for reducing anxiety in autistic youth. Method Searches of PubMed and Scopus databases were undertaken from January 1990 until December 2020. Studies were included if they consisted of randomised controlled trials (RCTs) using CBT to reduce anxiety in autistic youth. Separate random effects meta-analyses assessed anxiety ratings according to informant (clinician; parent; child), both at end-of-trial and at follow-up. Results A total of 19 RCTs met our inclusion criteria (833 participants: CBT N = 487; controls N = 346). Random effects meta-analyses revealed a large effect size for clinician rated symptoms (g = 0.88, 95% CI 0.55, 1.12, k = 11), while those for both parent (g = 0.40, 95% CI 0.24, 0.56; k = 18) and child-reported anxiety (g = 0.25, 95% CI 0.06, 0.43; k = 13) were smaller, but significant. These benefits were not however maintained at follow-up. Moderator analyses showed that CBT was more efficacious for younger children (for clinician and parent ratings) and when delivered as individual therapy (for clinician ratings). Using the Cochrane Risk of Bias 2 tool, we found concerns about reporting bias across most trials. Conclusions The efficacy of CBT for anxiety in autistic youth was supported in the immediate intervention period. However, substantial inconsistency emerged in the magnitude of benefit depending upon who was rating symptoms (clinician, parent or child). Follow-up analyses failed to reveal sustained benefits, though few studies have included this data. It will be important for future trials to address robustness of treatment gains overtime and to further explore inconsistency in efficacy by informant. We also recommend pre-registration of methods by trialists to address concerns with reporting bias.

Assessing the magnitude of reporting bias in a sample of recent systematic reviews - A comparison of a Prospero and Cochrane Sample

Objective: To explore differences in published reviews and their respective protocols in a sample of 97 non-Cochrane systematic reviews (non-CSRs) and 97 Cochrane systematic reviews (CSRs) in terms of PICOS elements and to which extent they were reported.Study Design and Setting: We searched PubMed and Cochrane database to identify non-CSRs and CSRs that were published in 2018. Afterwards we searched for their corresponding Cochrane or PROSPERO protocol. The reviews were compared to their protocols. The primary outcome was the change from protocol to review in terms of PICOS elements.Results: More than the half of each sample (54.6% of CSRs & 67% of non-CSRs) (ARR 12.4% [12% ; 12.8%]) presented changes in PICOS elements. A total of 227 changes were identified, distributed as 108 (47.5%) in CSRs and 119 (52.5%) in non-CSRs. For both samples an approximate third of total changes corresponded to changes related to primary outcomes. Marked differences were found between samples with regards to declaration of changes. Only 4.2% of changes in PICOS items have been declared in non-CSRs compared to 57.4% in CSRs (ARR 53.2% [52.9% ; 53.5%]).Conclusion: CSRs showed better results than non-CSRs in terms of reporting changes and showed higher quality. Nevertheless, reporting of changes from protocol should be advanced and requires improvement in general. Limitation of this study lies in its cross-sectional nature.

Trends in clinical trial registration in sub-Saharan Africa between 2010 and 2020: a cross-sectional review of three clinical trial registries

Objective Prospective registration of clinical trials is an ethical, scientific, and legal requirement that serves several functions, including minimising research wastage and publication bias. Sub-Saharan Africa (SSA) is increasingly hosting clinical trials over the past few years, and there is limited literature on trends in clinical trial registration and reporting in SSA. Therefore, we set out to determine the trends in clinical trials registered in SSA countries between 2010 and July 2020. Methods A cross-sectional study design was used to describe the type of clinical trials that are conducted in SSA from 1 January 2010 to 31 July 2020. The registries searched were ClinicalTrials.gov (CTG), the Pan African Clinical Trials Register (PACTR), and the International Standard Randomized Controlled Trial Number (ISRCTN). Data were extracted into Excel and imported into STATA for descriptive analysis. Results CTG had the highest number of registered trials at 2622, followed by PACTR with 1501 and ISRCTN with 507 trials. Trials were observed to increase gradually from 2010 and peaked at 2018–2019. Randomised trials were the commonest type, accounting for at least 80% across the three registries. Phase three trials investigating drugs targeted at infections/infestations were the majority. Few completed trials had their results posted: 58% in ISRCTN and 16.5% in CTG, thus suggesting reporting bias. Conclusion Despite the gradual increase in clinical trials registered during the period, recent trends suggest a drop in the number of trials registered across the region. Strengthening national and regional regulatory capacity will improve clinical trial registration and minimise reporting bias in completed clinical trials.

P–484 Progesterone supplementation in modified natural frozen embryo transfer (mNC-FET) does not cause mental health adverse effects - A sub-study of a multicenter RCT

Study question Do women undergoing mNC-FET with progesterone supplementation experience mental health adverse effects at a greater rate compared to a control group. Summary answer Progesterone supplementation does not affect mental wellbeing in women undergoing mNC-FET. What is known already Women and men undergoing assisted reproductive treatment more likely to experience stress and other adverse psychological effects than the background population. Various factors such as parental age, cause of infertility and treatment method have been shown to affect patient well-being. Progesterone supplementation is known to cause various physical adverse effects, yet few studies have investigated the potential mental health adverse effects of progesterone supplementation in FET. Study design, size, duration This is a sub-study of an ongoing RCT investigating the effect of luteal phase progesterone supplementation in mNC-FET. The aim is to investigate possible mental health adverse effects of progesterone. From 2019–2021 a total of 164 women were included (n = 84 and n = 82 in the progesterone and control group, respectively). The health and wellbeing self-reporting survey was fulfilled after randomization on hCG trigger + 11 days. Participants/materials, setting, methods A validated, electronic questionnaire in Danish was used to measure mental wellbeing in women aged 18–41 years undergoing mNC-FET with and without use of progesterone supplementation in the luteal phase at seven Danish public hospitals. Women were randomized to either progesterone treatment or no progesterone by a computerized randomization algorithm with minimization for female age > =37 years, previous oocyte retrievals and previous FET. Comparisons of survey responses were performed by chi-square tests. Main results and the role of chance The survey response rate was 68%. We observed no significant differences in any of the three items between the progesterone group and the control group. On the first item “to which degree have you felt sensitive due to treatment”, 56% and 52% responded “to a large degree” or “to some degree” sensitive in the progesterone vs. control group, while 25% and 34% vs. 19% and 13% responded “to a lesser extent” or “not at all” sensitive in progesterone vs. controls (P = 0.35). On the second item, “to which degree have you felt aggressive due to treatment”, 10% and 9% responded “to a large degree” or “to some degree”, 29% and 22% answered “to a lesser degree” and 62% and 70% responded “not at all” in the progesterone vs control group (P = 0.57). On the third item “to which degree have you cried unexpectedly due to treatment” 25% and 18% responded “to a large degree” or “to some degree” in the progesterone vs control group, 20% and 27% answered “to a lesser extent”, while 55% in both groups answered “not at all” (P = 0.44). Limitations, reasons for caution In a self-reported survey selection bias, due to a less than 100% response rate, and reporting bias cannot be excluded. However with the possibility to answer the survey online at leisure, the risk of reporting bias is minimized. Wider implications of the findings: A large concern for clinicians working with ART is patient wellbeing. Our study suggests that luteal phase support does not cause extra emotional distress, though further research is needed. Trial registration number NCT03795220

Peer review reduces spin in PCORI research reports

BACKGROUNDThe Patient-Centered Outcomes Research Institute (PCORI) is obligated to peer review and to post publicly “Final Research Reports” of all funded projects. Peer review emphasizes adherence to PCORI’s Methodology Standards. As part of meeting these standards, reviewers and editors seek to minimize “spin,” defined elsewhere as “reporting practices that distort the interpretation of results and mislead readers.” METHODSTwo independent raters assessed the prevalence of spin in reports submitted for PCORI peer review by April 2018. We then assessed whether authors addressed comments about spin received during peer review. Because investigators who submit research reports before publishing journal articles might incorporate PCORI’s feedback in their journal articles, we also assessed whether spin identified during PCORI peer review was present in related journal articles.RESULTSWe included 64 projects funded by PCORI. Spin was identified during peer review in 55/64 (86%) submitted research reports. Types of spin included reporting bias (46/55; 84%), inappropriate interpretation (40/55; 73%), inappropriate extrapolation of results (15/55; 27%), and inappropriate attribution of causality (5/55; 9%). Authors addressed comments about spin in 47/55 (85%) of the revised and accepted research reports.Journal articles associated with 21/55 (38%) research reports contained spin that was also identified in the research report. PCORI comments about spin were potentially applicable to 44/110 journal articles with results. Of these, 27/44 (61%) contained spin that was also identified in the PCORI research report. The proportion of articles with spin was similar for those accepted before and after PCORI peer review.DISCUSSIONMost reports submitted to PCORI included spin, which was mitigated during peer review. We found no evidence that peer review of PCORI research reports affected spin in journal articles. Some journal articles contained spin even when authors removed spin from their PCORI research reports.When both are available, PCORI research reports might be more useful to systematic reviewers and other stakeholders compared with journal articles about the same study because they include less reporting bias and other types of spin.

Misreporting of Results of Research in Psychiatry

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P < .001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature.

Collider and Reporting Biases Involved in the Analyses of Cause of Death Associations in Death Certificates: an Illustration with Cancer and Suicide

Background: Data from death certificates have been studied to explore causal associations between diseases. However, these analyses are subject to collider and reporting biases (selection and information biases, respectively). Methods: We aimed to assess to what extent associations of causes of death estimated from individual mortality data can be extrapolated to the general population. We used a multistate model to generate populations of individuals and simulate their health states up to death from national health statistics and artificially replicate collider bias. Associations between health states can then be estimated from such simulated deaths by logistic regression and the magnitude of collider bias assessed. Reporting bias can be approximated by comparing the estimates obtained from the observed death certificates (subject to collider and reporting biases) with those obtained from the simulated deaths (subject to collider bias only). Results: As an illustrative example, we estimated the association between cancer and suicide in French death certificates, and found that cancer was negatively associated with suicide. Collider bias, due to conditioning inclusion in the study population on death, increasingly downwarded the associations with cancer site lethality. Reporting bias was much stronger than collider bias and depended on the cancer site, but not prognosis. Conclusions: These results argue for an assessment of the magnitude of both collider and reporting biases before performing analyses of cause of death associations exclusively from death certificates. If these biases cannot be corrected, results from these analyses should not be extrapolated to the general population.

Correcting for outcome reporting bias in a meta-analysis: A meta-regression approach

Outcome reporting bias (ORB) refers to the biasing effect caused by researchers selectively reporting outcomes based on their statistical significance. ORB leads to inflated average effect size estimates in a meta-analysis if only the outcome with the largest effect size is reported due to ORB. We propose a new method (CORB) to correct for ORB that includes an estimate of the variability of the outcomes' effect size as a moderator in a meta-regression model. An estimate of the variability of the outcomes' effect size can be computed by assuming a correlation among the outcomes. Results of a Monte-Carlo simulation study showed that effect size in meta-analyses may be severely overestimated without any correction for ORB. The CORB method accurately estimates effect size when overestimation caused by ORB is the largest. Applying the new method to a meta-analysis on the effect of playing violent video games on aggressive cognition showed that the average effect size estimate decreased when correcting for ORB. We recommend to routinely apply methods to correct for ORB in any meta-analysis. We provide annotated R code and functions to facilitate researchers to apply the CORB method.