Developing survey weights to ensure representativeness in a national, matched cohort study: results from the Children and young people with Long Covid (CLoCk) study. (preprint)

Background: Findings from studies assessing Long Covid in children and young people (CYP) need to be viewed in light of their methodological limitations. For example, if non-response and/or attrition over time systematically differ by sub-groups of CYP, findings could be biased and generalisation limited. The present study aimed to (i) construct survey weights for the Children and young people with Long Covid (CLoCk) study, and (ii) apply them to published CLoCk findings showing the prevalence of shortness of breath and tiredness increased over time from baseline to 12-months post-baseline in both SARS-CoV-2 Positive and Negative CYP. Methods: Logistic regression was used to compute the probability of (i) Responding given envisioned to take part, (ii) Responding timely given responded, and (iii) (Re)infection given timely response. Response, timely response and (re)infection weights were generated as the reciprocal of the corresponding probability, with an overall ‘envisioned population’ survey weight derived as the product of these weights. Survey weights were trimmed, and an interactive tool developed to re-calibrate target population survey weights to the general population using data from the 2021 UK Census. Results: Flexible survey weights for the CLoCk study were successfully developed. In the illustrative example re-weighted results (when accounting for selection in response, attrition, and (re)infection) were consistent with published findings. Conclusions: Flexible survey weights to address potential bias and selection issues were created for and used in the CLoCk study. Previously reported prospective findings from CLoCk are generalisable to the wider population of CYP in England. This study highlights the importance of considering selection into a sample and attrition over time when considering generalisability of findings.

Can we mitigate the psychological impacts of social isolation using behavioural activation? Long-term results of the UK BASIL Urgent Public Health COVID-19 pilot randomised controlled trial and living systematic review (preprint)

BackgroundBehavioural and cognitive interventions remain a credible approach in preventing loneliness and depression. There was a need to rapidly generate and assimilate trial-based data during COVID-19. ObjectivesWe undertook a COVID-19 parallel pilot RCT of behavioural activation for depression and loneliness [the BASIL-C19 trial ISRCTN94091479]. We also assimilate these data in a COVID-19 living systematic review [PROSPERO CRD42021298788]. MethodsPrimary care participants (>=65 years) with long-term conditions were computer randomised to Behavioural Activation (n=47) versus care-as-usual (n=49). The single blinded primary outcome was the PHQ-9. Secondary outcomes included loneliness (De Jong Gierveld Scale). Data from the BASIL-C19 trial were included in a random effects meta-analysis of depression and loneliness. FindingsThe 12 months adjusted mean difference for PHQ-9 was -0.70 (95% CI -2.61 to 1.20) and for loneliness was -0.39 (95% CI -1.43 to 0.65). Secondary 12-month trial outcomes suggested evidence of benefit for behavioural activation. The BASIL-C19 meta-analysis (13 trials) found short-term reductions in depression (standardised mean difference [SMD]=-0.31, 95%CI -0.51 to -0.11) and loneliness (SMD=-0.48, 95%CI -0.70 to -0.27). There were few long-term trials, but there was evidence of some benefit (loneliness SMD=-0.20, 95%CI -0.40 to -0.01; depression SMD=-0.20, 95%CI -0.47 to 0.07). DiscussionWe found a signal of effect in reducing loneliness and depression in the BASIL trial. Living meta-analysis provides strong evidence of short-term benefit for loneliness and depression. Clinical implicationsScalable behavioural and cognitive approaches should be considered as population-level strategies for depression and loneliness on the basis of the living systematic review. FundingThis study was funded by National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research (PGfAR) RP-PG-0217-20006. Author summaryO_ST_ABSWhy was this study done?C_ST_ABS Older people with long-term conditions have been impacted by COVID-19 pandemic restrictions and have experienced social isolation. In turn, this puts them at risk for depression and loneliness, and these are bad for health and wellbeing. Psychosocial approaches, such as behavioural activation, could be helpful. Trial-based evidence is needed to demonstrate if it is possible to prevent the onset, or mitigate the impact, of loneliness and depression. There are few studies of brief psychosocial interventions to mitigate depression and loneliness, and it is important to know how emerging trial-based data adds to existing evidence. What did the researchers do and find? There was preliminary evidence that levels of loneliness were reduced at 3 months when behavioural activation was offered. At longer term (12-month) follow-up there were signals of ongoing positive impact. When BASIL-C19 data were assimilated into a living systematic review there is clear evidence of impact of brief psychological interventions on depression and loneliness in the short-term. More research into the longer-term impact is needed. What does all this mean? Behavioural activation now shows evidence of benefit which will be useful for policy makers in offering support to people who are socially isolated. This research knowledge will be useful once the COVID-19 pandemic has passed, since loneliness is common in older populations and effective scalable solutions will be needed to tackle this problem. As new trial-based data emerges, our living systematic review and meta-analysis will be updated since this is an area of active research.

Developing a model for predicting impairing physical symptoms in children 3 months after a SARS-CoV-2 PCR-test: The CLoCk Study (preprint)

Abstract Importance: Predictive models can help identify SARS-CoV-2 patients at greatest risk of post-COVID sequelae and direct them towards appropriate care. Objective: To develop and internally validate a model to predict children and young people most likely to experience at least one impairing physical symptom 3 months after a SARS-CoV-2 PCR-test and to determine whether the impact of these predictors differed by SARS-CoV-2 infection status. Design: Potential pre-specified predictors included: SARS-CoV-2 status, sex, age, ethnicity, deprivation, quality of life/functioning (5 EQ-5D-Y items), physical and mental health, and loneliness (all prior to SARS-CoV-2 testing), and number of physical symptoms at testing. Logistic regression was used to develop the model. Model performance was assessed using calibration and discrimination measures; internal validation was performed via bootstrapping; the final model was adjusted for overfitting. Setting: National cohort study of SARS-CoV-2 PCR-positive and PCR-negative participants matched according to age, sex, and geographical area. Participants: Children and young people aged 11-17 years who were tested for SARS-CoV-2 infection in England, January to March 2021. Main outcome measure: one or more physical symptom 3 months after initial PCR-testing which affected physical, mental or social well-being and interfered with daily living. Results: A total of 50,836 children and young people were approached; 7,096 (3,227 test-positives, 3,869 test-negatives) who completed a questionnaire 3 months after their PCR-test were included. 39.6% (1,279/3,227) of SAR-CoV-2 PCR-positives and 30.6% (1,184/3,869) of SAR-CoV-2 PCR-negatives had at least one impairing physical symptom 3 months post-test. The final model contained predictors: SARS-COV-2 status, number of symptoms at testing, sex, age, ethnicity, self-rated physical and mental health, feelings of loneliness and four EQ-5D-Y items before testing. Internal validation showed minimal overfitting with excellent calibration and discrimination measures (optimism adjusted calibration slope:0.97527; C-statistic:0.83640). Conclusions and relevance: We developed a risk prediction equation to identify those most at risk of experiencing at least one impairing physical symptom 3 months after a SARS-CoV-2 PCR-test which could serve as a useful triage and management tool for children and young people during the ongoing pandemic. External validation is required before large-scale implementation.

Persistent Symptoms Following SARS-CoV-2 Infection Among Children and Young People: A Meta-Analysis of Controlled and Uncontrolled Studies (preprint)

Background: Data on the long-term impact of SARS-CoV-2 infection in children and young people (CYP) is conflicting. We assessed evidence on long-term post-COVID symptoms in CYP examining prevalence, risk factors, type and duration.Methods: Systematic search of published and unpublished literature using 13 online databases between 01/12/2019 – 31/07/2021. Eligible studies reported CYP ≤19 years with confirmed or probable SARS-CoV-2 with any symptoms persisting beyond acute illness. Random effects meta-analyses examined pooled risk difference in symptom prevalence (controlled studies only) and pooled prevalence (uncontrolled studies also included). Meta-regression examined study characteristics hypothesised to be associated with symptom prevalence. Prospectively registered: CRD42021233153. Findings: Twenty two of 3357 unique studies were eligible, including 23,141 CYP. Median duration of follow-up was 125 days (IQR 99-231).Pooled risk difference in post-COVID cases compared to controls (5 studies) were significantly higher for cognitive difficulties (3% (95% CI 1, 4)), headache (5% (1, 8)), loss of smell (8%, (2, 15)), sore throat (2% (1, 2)) and sore eyes (2% (1, 3)) but not abdominal pain, cough, fatigue, myalgia, insomnia, diarrhoea, fever, dizziness or dyspnoea.Pooled prevalence of symptoms in post-COVID participants in 17 studies ranged from 15% (diarrhoea) to 47% (fatigue). Age was associated with higher prevalence of all symptoms except cough. Higher study quality was associated with lower prevalence of all symptoms, except loss of smell and cognitive symptoms.Interpretation: The frequency of the majority of reported persistent symptoms was similar in SARS-CoV-2 positive cases and controls. This systematic review and meta-analysis highlights the critical importance of a control group in studies on CYP post SARS-CoV-2 infection.Funding: None to declare. Declaration of Interest: SAB, RS, SDB, AXDZ, LLO, SNL, BLDS, RMV and OVS have no conflicts of interest. TJS is the Chair of the Health Research Authority for England who reimburse his university for his time. He is not paid personally. He has recused himself from research studies in which he is personally involved and which require ethical approval from the HRA.