A tailored psychological intervention for anxiety and depression management in people with chronic obstructive pulmonary disease: TANDEM RCT and process evaluation.

Background: People with chronic obstructive pulmonary disease have high levels of anxiety and depression, which is associated with increased morbidity and poor uptake of effective treatments, such as pulmonary rehabilitation. Cognitive-behavioural therapy improves mental health of people with long-term conditions and could potentially increase uptake of pulmonary rehabilitation, enabling synergies that could enhance the mental health of people with chronic obstructive pulmonary disease. Aim: Our aim was to develop and evaluate the clinical effectiveness and cost effectiveness of a tailored cognitive-behavioural approach intervention, which links into, and optimises the benefits of, routine pulmonary rehabilitation. Design: We carried out a pragmatic multicentre randomised controlled trial using a 1.25 : 1 ratio (intervention : control) with a parallel process evaluation, including assessment of fidelity. Setting: Twelve NHS trusts and five Clinical Commissioning Groups in England were recruited into the study. The intervention was delivered in participant's own home or at a local NHS facility, and by telephone. Participants: Between July 2017 and March 2020 we recruited adults with moderate/very severe chronic obstructive pulmonary disease and mild/moderate anxiety and/or depression, meeting eligibility criteria for assessment for pulmonary rehabilitation. Carers of participants were invited to participate. Intervention: The cognitive-behavioural approach intervention (i.e. six to eight 40- to 60-minute sessions plus telephone support throughout pulmonary rehabilitation) was delivered by 31 trained respiratory healthcare professionals to participants prior to commencing pulmonary rehabilitation. Usual care included routine pulmonary rehabilitation referral. Main outcome measures: Co-primary outcomes were Hospital Anxiety and Depression Scale - anxiety and Hospital Anxiety and Depression Scale - depression at 6 months post randomisation. Secondary outcomes at 6 and 12 months included health-related quality of life, smoking status, uptake of pulmonary rehabilitation and healthcare use. Results: We analysed results from 423 randomised participants (intervention, n = 242; control, n = 181). Forty-three carers participated. Follow-up at 6 and 12 months was 93% and 82%, respectively. Despite good fidelity for intervention delivery, mean between-group differences in Hospital Anxiety and Depression Scale at 6 months ruled out clinically important effects (Hospital Anxiety and Depression Scale - anxiety mean difference -0.60, 95% confidence interval -1.40 to 0.21; Hospital Anxiety and Depression Scale - depression mean difference -0.66, 95% confidence interval -1.39 to 0.07), with similar results at 12 months. There were no between-group differences in any of the secondary outcomes. Sensitivity analyses did not alter these conclusions. More adverse events were reported for intervention participants than for control participants, but none related to the trial. The intervention did not generate quality-of-life improvements to justify the additional cost (adjusted mean difference £770.24, 95% confidence interval -£27.91 to £1568.39) to the NHS. The intervention was well received and many participants described positive affects on their quality of life. Facilitators highlighted the complexity of participants' lives and considered the intervention to be of potential valuable; however, the intervention would be difficult to integrate within routine clinical services. Our well-powered trial delivered a theoretically designed intervention with good fidelity. The respiratory-experienced facilitators were trained to deliver a low-intensity cognitive-behavioural approach intervention, but high-intensity cognitive-behavioural therapy might have been more effective. Our broad inclusion criteria specified objectively assessed anxiety and/or depression, but participants were likely to favour talking therapies. Randomisation was concealed and blinding of outcome assessment was breached in only 15 participants. Conclusions: The tailored cognitive-behavioural approach intervention delivered with fidelity by trained respiratory healthcare professionals to people with chronic obstructive pulmonary disease was neither clinically effective nor cost-effective. Alternative approaches that are integrated with routine long-term condition care are needed to address the unmet, complex clinical and psychosocial needs of this group of patients. Trial registration: This trial is registered as ISRCTN59537391. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/146/02) and is published in full in Health Technology Assessment; Vol. 28, No. 1. See the NIHR Funding and Awards website for further award information.

People with long-standing lung problems, such as chronic obstructive pulmonary disease, often also have anxiety and depression, which further reduces their quality of life. Two existing treatments could help. Pulmonary rehabilitation (a programme of exercise and education) improves both the physical and mental health of people with chronic obstructive pulmonary disease. Cognitive­behavioural therapy (a talking therapy) may reduce anxiety and depression. The TANDEM [Tailored intervention for Anxiety and Depression Management in chronic obstructive pulmonary disease (COPD)] intervention linked these two treatments by providing talking therapy based on cognitive­behavioural therapy during the waiting time following referral for pulmonary rehabilitation. The TANDEM treatment was delivered by respiratory healthcare professionals (e.g. nurses or physiotherapists) trained to deliver the talking therapy in six to eight weekly sessions. The sessions were conducted in the participant's home (or another convenient location), with brief telephone support during the pulmonary rehabilitation. Of 423 participants recruited to the study, 242 participants received TANDEM talking therapy and 181 participants received usual care (including a referral to pulmonary rehabilitation). We measured mental health, quality of life, social life, attendance at pulmonary rehabilitation and healthcare use in both groups at 6 and 12 months. Forty-three carers joined the study and we assessed their mental well-being. We interviewed patients, carers and health professionals to find out their views and experience of the TANDEM treatment. We also examined whether or not the TANDEM treatment was good value for money. The TANDEM treatment did not improve the mental or the physical health of people with chronic obstructive pulmonary disease. In addition, the TANDEM treatment cost the NHS an extra £770 per patient, which was not good value for money. The TANDEM treatment was well received, and many participants told us how it had helped them. Heath-care professionals noted how participants did not just have chronic obstructive pulmonary disease, but were coping with many physical, mental and social problems. The TANDEM intervention was not effective and, therefore, other strategies will be needed to help people with chronic obstructive pulmonary disease and mental health problems live with their condition.

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.

Tailored, psychological intervention for anxiety and/or depression in people with chronic obstructive pulmonary disease (COPD), TANDEM (Tailored intervention for ANxiety and DEpression Management in COPD): statistical analysis plan for a randomised controlled trial.

BACKGROUND: The aim of the TANDEM trial is to evaluate whether a tailored, psychological cognitive behavioural approach intervention, which links into, and optimises the effects of routine pulmonary rehabilitation (PR), leads to a reduction in mild/moderate anxiety and/or depression in people with moderate, severe or very severe chronic obstructive pulmonary disease. METHODS AND DESIGN: TANDEM is a multi-centre, two-arm, parallel group, pragmatic, individually randomised controlled, superiority trial including an internal pilot. Participants are randomised to receive either the intervention (a tailored psychological intervention plus usual care including referral to PR) or the control (usual care including referral to PR). The designed randomisation ratio is 1.25:1 in favour of the intervention. The multiple-primary outcomes are participant depression and anxiety at 6 months, measured using the Hospital Anxiety and Depression Scale (HADS) depression and anxiety subscales. RESULTS: This article describes the statistical analysis plan (SAP) for the TANDEM trial. In particular, we describe the general analysis principles, how we will handle missing data, the primary and secondary outcomes and how these will be analysed, sensitivity analyses for the multiple-primary outcomes, and any other analyses and data summaries. The SAP was developed and published prior to completion of follow-up of the last participant. TRIAL REGISTRATION: ISRCTN registry ISRCTN59537391. Registered on 20 March 2017.

Tailored, psychological intervention for anxiety or depression in people with chronic obstructive pulmonary disease (COPD), TANDEM (Tailored intervention for ANxiety and DEpression Management in COPD): protocol for a randomised controlled trial.

BACKGROUND: People with chronic obstructive pulmonary disease (COPD) are at increased risk of depression and anxiety, which greatly reduces their quality of life and is associated with worse outcomes; but these psychological co-morbidities are under-recognised and undertreated in COPD patients. Pulmonary rehabilitation (PR) improves mood for up to 6 months but health practitioners under-refer, and patients commonly fail to attend/complete PR. Research suggests that complex non-pharmacological interventions, including both psychological and exercise components, may reduce anxiety and depression in COPD. We have developed a tailored, cognitive behavioural approach (CBA) intervention for patients with COPD and co-morbid anxiety and/or depression ('TANDEM'), which precedes and optimises the benefits of currently offered PR. We hypothesise that such a psychological intervention, delivered by supervised, trained respiratory healthcare professionals, will improve mood in patients with mild to moderate anxiety and/or depression and encourage uptake and completion of PR. METHODS: We will conduct a multi-centre, pragmatic, randomised controlled trial of the TANDEM intervention compared to usual care across the Midlands, London, the South East and Bristol, UK. We will train healthcare professionals familiar with COPD to deliver the manualised, tailored, face-to-face, one-to-one intervention weekly for 6-8 weeks. We will recruit 430 participants from primary, community and secondary care with confirmed COPD and moderate to very severe airflow limitation, who are eligible for assessment for PR, and who screen positive for symptoms of mild/moderate depression and/or anxiety using the Hospital Anxiety and Depression scale (HADS). Participants will be randomised 1.25:1 (intervention: usual care). The co-primary outcomes are the HADS anxiety and depression subscale scores at 6 months; participants will be followed up to 12 months. Secondary outcomes include uptake and completion of PR and healthcare resource use. There will be a parallel process evaluation and a health economic evaluation. DISCUSSION: The TANDEM intervention has the potential to optimise the unrealised synergy between a psychological intervention and PR. The CBA sessions will precede PR and target individuals' cognitions, behaviours and symptoms associated with anxiety and depression to decrease psychological morbidity and increase effective self-management amongst patients with COPD. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN59537391. Registered on 20 March 2017. Protocol version 6.0, 22 April 2018.

Assessment of PARP4 as a candidate breast cancer susceptibility gene.

PURPOSE: PARP4 has been proposed as a candidate breast cancer susceptibility gene. However, its function and involvement in breast carcinogenesis is unclear. We sought to determine the variant frequency of PARP4 in BRCA-negative women referred for genetic testing from Singapore and to perform functional analyses of PARP4. METHODS: Next-generation sequencing of PARP4 was conducted for 198 BRCA-negative cases from Singapore. Three independent case-control association analyses of PARP4 were performed for (1) our Singaporean cohort, (2) three dbGaP datasets, and (3) cases from TCGA, with controls from the Exome Aggregation Consortium (ExAC). PARP4 knockout cells were generated utilizing the CRISPR-Cas9 approach in MDA-MB-231 (breast cancer) and MCF10A (normal breast) cell lines, and colony formation, cell proliferation, and migration assays carried out. RESULTS: Candidate variants in PARP4 were identified in 5.5% (11/198) of our Singapore cohort. Case-control association studies for our cases and the dbGaP datasets showed no significant association. However, a significant association was observed for PARP4 variants when comparing 988 breast cancer cases from the TCGA provisional data and 53,105 controls from ExAC (ALL) (OR 0.249, 95% CI 0.139-0.414, P = 2.86 × 10-11). PARP4 knockout did not affect the clonogenicity, proliferation rate, and migration of normal breast cells, but appeared to decrease the proliferation rate and clonogenicity of breast cancer cells. CONCLUSIONS: Taken together, our results do not support that PARP4 functions as a cancer susceptibility gene. This study highlights the importance of performing functional analyses for candidate cancer predisposition genes.