ABSTRACT
The identification of surrogate markers for gold standard outcomes in clinical trials enables future cost-effective trials that target the identified markers. Due to resource limitations, these surrogate markers may be collected only for cases and for a subset of the trial cohort, giving rise to what is termed the case-cohort design. Motivated by a COVID-19 vaccine trial, we propose methods of assessing the surrogate markers for a time-to-event outcome in a case-cohort design by using mediation and instrumental variable (IV) analyses. In the mediation analysis we decomposed the vaccine effect on COVID-19 risk into an indirect effect (the effect mediated through the surrogate marker such as neutralizing antibodies) and a direct effect (the effect not mediated by the marker), and we propose that the mediation proportions are surrogacy indices. In the IV analysis we aimed to quantify the causal effect of the surrogate marker on disease risk in the presence of surrogatedisease confounding which is unavoidable even in randomized trials. We employed weighted estimating equations derived from nonparametric maximum likelihood estimators (NPMLEs) under semiparametric probit models for the time-to-disease outcome. We plugged in the weighted NPMLEs to construct estimators for the aforementioned causal effects and surrogacy indices, and we determined the asymptotic properties of the proposed estimators. Finite sample performance was evaluated in numerical simulations. Applying the proposed mediation and IV analyses to a mock COVID-19 vaccine trial data, we found that 84.2% of the vaccine efficacy was mediated by 50% pseudovirus neutralizing antibody and that neutralizing antibodies had significant protective effects for COVID-19 risk.
ABSTRACT
Background/Aims Rheumatic and musculoskeletal diseases (RMDs) are some of the most common indications for prescribed opioids. It is unclear how opioid prescribing has changed in the UK for RMDs, especially during the COVID-19 pandemic with limited healthcare access and cancelled elective-surgical interventions, which could impact prescribing in either direction. We aimed to investigate trends in opioid prescribing in RMDs and assess the impact of the pandemic in the UK. Methods Adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (AxSpA), systemic lupus erythematosus (SLE), osteoarthritis (OA) and fibromyalgia with opioid prescriptions between 01/Jan/2006-31/Aug/2021 without prior cancer in the UK Clinical Practice Research Datalink (CPRD) were included. We calculated ageand gender-standardised yearly rates of people with opioid prescriptions between 2006-2021, and identified change points in trends by checking whether the rate of change of standardised rates crossed zero. For people with opioid prescriptions, monthly measures of mean morphine milligram equivalents (MME)/day were calculated between 2006-2021. To assess the impact of the pandemic, we fitted regression models to the monthly number of people with opioid prescriptions between Jan/2015-Aug/2021. The time coefficient reflects the trend pre-pandemic and the interaction term coefficient represents the change in the trend during the pandemic. Results We included 1,313,519 patients: 36,932 with RA, 12,649 with PsA, 6,811 with AxSpA, 6,423 with SLE, 1,255,999 with OA, and 66,944 with fibromyalgia. People with opioid prescriptions increased from 2006 to 2018 for OA, to 2019 for RA, AxSpA and SLE, to 2020 for PsA, and to 2021 for fibromyalgia, and all plateaued/decreased afterwards. OA patients on opioids increased from 466.8/10,000 persons in 2006 to a peak of 703.0 in 2018, followed by a decline to 575.3 in 2021. From 2006 to 2021, there was a 4.5-fold increase in fibromyalgia opioid users (17.7 vs.78.5/10,000 persons). In this period, MME/day increased for all RMDs, with the highest for fibromyalgia (>=35). During COVID-19 lockdowns, RA, PsA and fibromyalgia showed significant changes in the trend of people with opioid prescriptions. With a decreasing trend for RA (-0.001,95%CI=-0.002,-0.001) and a decreasing-to-flat curve for PsA (0.0010,95%CI=0.0006,0.0015) prepandemic until Feb/2020, the trends changed by -0.005 (95%CI=-0.008,-0.002) for RA and -0.003 (95%CI=-0.006,-0.0003) for PsA, leading to steeper decreasing trends during the pandemic (Mar/2020-Aug/2021). Fibromyalgia, conversely, had an increasing trend (0.009,95%CI=0.008,0.009) pre-pandemic, and this trend started decreasing by -0.009 (95%CI=-0.011,-0.006) during the pandemic. Conclusion The plateauing/decreasing trend of people with opioid prescriptions in RMDs after 2018 may reflect the efforts to tackle the rising opioid prescribing in UK primary care. Of all RMDs, fibromyalgia patients had the highest MME/day throughout the study period. COVID-19 lockdowns contribute to fewer people on opioids for most RMDs, reassuring there was no sudden increase in opioid prescribing during the pandemic.
ABSTRACT
Purpose: This study compared Cognitive-Behavioral Therapy (CBT), Mindfulness-Based Cognitive Therapy (MBCT), and Activity-based Supportive Counselling (treatment-as-usual;TAU) for reducing delinquency, psychological risk factors, mental health symptoms, and improving the quality of life among at-risk youths in Hong Kong outreaching social services. Methods: In this quasi-experimental study, non-custodial youths with delinquency and mental health issues underwent eight sessions of CBT (n = 24), MBCT (n = 30), or TAU (n = 61). Results: Dependent-sample t-test showed CBT reduced mental health symptoms and delinquency. TAU reduced mental health symptoms and improved quality of life. MBCT resulted in no significant change. Time x group ANCOVA underscored TAU in improving quality of life. Hierarchical linear regression showed decreases in delinquency and mental health symptoms mediated by decreases in psychological risk factors. Discussion: Results suggest that outreaching social service agencies in Hong Kong could enhance their intervention by augmenting the sports and leisure activities of TAU with structured CBT programs.