Publications by authors named "Tom Palmer"

75 Publications

Effectiveness of conditional cash transfers (Afya credits incentive) to retain women in the continuum of care during pregnancy, birth and the postnatal period in Kenya: a cluster-randomised trial.

BMJ Open 2022 Jan 6;12(1):e055921. Epub 2022 Jan 6.

Institute for Global Health, University College London, London, UK.

Objectives: Given high maternal and child mortality rates, we assessed the impact of conditional cash transfers (CCTs) to retain women in the continuum of care (antenatal care (ANC), delivery at facility, postnatal care (PNC) and child immunisation).

Design: We conducted an unblinded 1:1 cluster-randomised controlled trial.

Setting: 48 health facilities in Siaya County, Kenya were randomised. The trial ran from May 2017 to December 2019.

Participants: 2922 women were recruited to the control and 2522 to the intervention arm.

Interventions: An electronic system recorded attendance and triggered payments to the participant's mobile for the intervention arm (US$4.5), and phone credit for the control arm (US$0.5). Eligibility criteria were resident in the catchment area and access to a mobile phone.

Primary Outcomes: Primary outcomes were any ANC, delivery, any PNC between 4 and 12 months after delivery, childhood immunisation and referral attendance to other facilities for ANC or PNC. Given problems with the electronic system, primary outcomes were obtained from maternal clinic books if participants brought them to data extraction meetings (1257 (50%) of intervention and 1053 (36%) control arm participants). Attendance at referrals to other facilities is not reported because of limited data.

Results: We found a significantly higher proportion of appointments attended for ANC (67% vs 60%, adjusted OR (aOR) 1.90; 95% CI 1.36 to 2.66) and child immunisation (88% vs 85%; aOR 1.74; 95% CI 1.10 to 2.77) in intervention than control arm. No intervention effect was seen considering delivery at the facility (90% vs 92%; aOR 0.58; 95% CI 0.25 to 1.33) and any PNC attendance (82% vs 81%; aOR 1.25; 95% CI 0.74 to 2.10) separately. The pooled OR across all attendance types was 1.64 (1.28 to 2.10).

Conclusions: Demand-side financing incentives, such as CCTs, can improve attendance for appointments. However, attention needs to be paid to the technology, the barriers that remain for delivery at facility and PNC visits and encouraging women to attend ANC visits within the recommended WHO timeframe.

Trial Registration: NCT03021070.
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http://dx.doi.org/10.1136/bmjopen-2021-055921DOI Listing
January 2022

Prevalence and duration of detectable SARS-CoV-2 nucleocapsid antibodies in staff and residents of long-term care facilities over the first year of the pandemic (VIVALDI study): prospective cohort study in England.

Lancet Healthy Longev 2022 Jan 16;3(1):e13-e21. Epub 2021 Dec 16.

UCL Institute of Health Informatics, London, UK.

Background: Long-term care facilities (LTCFs) have reported high SARS-CoV-2 infection rates and related mortality, but the proportion of infected people among those who have survived, and duration of the antibody response to natural infection, is unknown. We determined the prevalence and stability of nucleocapsid antibodies (the standard assay for detection of previous infection) in staff and residents in LTCFs in England.

Methods: This was a prospective cohort study of residents 65 years or older and of staff 65 years or younger in 201 LTCFs in England between March 1, 2020, and May 7, 2021. Participants were linked to a unique pseudo-identifier based on their UK National Health Service identification number. Serial blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid protein using the Abbott ARCHITECT i-system (Abbott, Maidenhead, UK) immunoassay. Primary endpoints were prevalence and cumulative incidence of antibody positivity, which were weighted to the LTCF population. Incidence rate of loss of antibodies (seroreversion) was estimated from Kaplan-Meier curves.

Findings: 9488 samples were included, 8636 (91·0%) of which could be individually linked to 1434 residents and 3288 staff members. The cumulative incidence of nucleocapsid seropositivity was 34·6% (29·6-40·0) in residents and 26·1% (23·0-29·5) in staff over 11 months. 239 (38·6%) residents and 503 women (81·3%) were included in the antibody-waning analysis, and median follow-up was 149 days (IQR 107-169). The incidence rate of seroreversion was 2·1 per 1000 person-days at risk, and median time to reversion was 242·5 days.

Interpretation: At least a quarter of staff and a third of surviving residents were infected with SAR-CoV-2 during the first two waves of the pandemic in England. Nucleocapsid-specific antibodies often become undetectable within the first year following infection, which is likely to lead to marked underestimation of the true proportion of people with previous infection. Given that natural infection might act to boost vaccine responses, better assays to identify natural infection should be developed.

Funding: UK Government Department of Health and Social Care.
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http://dx.doi.org/10.1016/S2666-7568(21)00282-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8676418PMC
January 2022

Understanding the Lived Experience of Children With Type 1 Diabetes in Kenya: Daily Routines and Adaptation Over Time.

Qual Health Res 2022 01 27;32(1):145-158. Epub 2021 Nov 27.

Institute for Global Health, 4919University College London, London, UK.

Focusing only on biomedical targets neglects the important role that psychosocial factors play in effective diabetes self-management. This study aims to understand the lived experiences of children with Type 1 Diabetes (T1DM) in Kenya. Children ( = 15) participated in focus group discussions and photo diary data collection. Focus group discussions and semi-structured interviews were also conducted with caregivers ( = 14). We describe an adaptation to diabetes over time, identifying four overarching themes: knowledge and awareness, economic exclusion, the importance of social support, and striving for normality. Photo diaries are then categorized to explore daily realities of diabetes management. Children with T1DM in Kenya face varied barriers to care but can lead a "normal" and fulfilling life, provided adequate support is in place. To improve the lives of children with diabetes in this context and others like it, stakeholders must take note of children's experiences and recognize their multidimensional needs.
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http://dx.doi.org/10.1177/10497323211049775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721679PMC
January 2022

Changes in COVID-19 outbreak severity and duration in long-term care facilities following vaccine introduction, England, November 2020 to June 2021.

Euro Surveill 2021 11;26(46)

UCL Institute of Health Informatics, London, United Kingdom.

We describe the impact of changing epidemiology and vaccine introduction on characteristics of COVID-19 outbreaks in 330 long-term care facilities (LTCF) in England between November 2020 and June 2021. As vaccine coverage in LTCF increased and national incidence declined, the total number of outbreaks and outbreak severity decreased across the LTCF. The number of infected cases per outbreak decreased by 80.6%, while the proportion of outbreaks affecting staff only increased. Our study supports findings of vaccine effectiveness in LTCF.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.46.2100995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603404PMC
November 2021

Improving access to diabetes care for children: An evaluation of the changing diabetes in children project in Kenya and Bangladesh.

Pediatr Diabetes 2021 Oct 28. Epub 2021 Oct 28.

Institute for Global Health, University College London, London, UK.

Background: The changing diabetes in children (CDiC) project is a public-private partnership implemented by Novo Nordisk, to improve access to diabetes care for children with type 1 diabetes. This paper outlines the findings from an evaluation of CDiC in Bangladesh and Kenya, assessing whether CDiC has achieved its objectives in each of six core program components.

Research Design And Methods: The Rapid Assessment Protocol for Insulin Access (RAPIA) framework was used to analyze the path of insulin provision and the healthcare infrastructure in place for diagnosis and treatment of diabetes. The RAPIA facilitates a mixed-methods approach to multiple levels of data collection and systems analysis. Information is collected through questionnaires, in-depth interviews and focus group discussions, site visits, and document reviews, engaging a wide range of stakeholders (N = 127). All transcripts were analyzed thematically.

Results: The CDiC scheme provides a stable supply of free insulin to children in implementing facilities in Kenya and Bangladesh, and offers a comprehensive package of pediatric diabetes care. However, some elements of the CDiC program were not functioning as originally intended. Transitions away from donor funding and toward government ownership are a particular concern, as patients may incur additional treatment costs, while services offered may be reduced. Additionally, despite subsidized treatment costs, indirect costs remain a substantial barrier to care.

Conclusion: Public-private partnerships such as the CDiC program can improve access to life-saving medicines. However, our analysis found several limitations, including concerns over the sustainability of the project in both countries. Any program reliant on external funding and delivered in a high-turnover staffing environment will be vulnerable to sustainability concerns.
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http://dx.doi.org/10.1111/pedi.13277DOI Listing
October 2021

Optima TB: A tool to help optimally allocate tuberculosis spending.

PLoS Comput Biol 2021 09 27;17(9):e1009255. Epub 2021 Sep 27.

University College London, London, United Kingdom.

Approximately 85% of tuberculosis (TB) related deaths occur in low- and middle-income countries where health resources are scarce. Effective priority setting is required to maximise the impact of limited budgets. The Optima TB tool has been developed to support analytical capacity and inform evidence-based priority setting processes for TB health benefits package design. This paper outlines the Optima TB framework and how it was applied in Belarus, an upper-middle income country in Eastern Europe with a relatively high burden of TB. Optima TB is a population-based disease transmission model, with programmatic cost functions and an optimisation algorithm. Modelled populations include age-differentiated general populations and higher-risk populations such as people living with HIV. Populations and prospective interventions are defined in consultation with local stakeholders. In partnership with the latter, demographic, epidemiological, programmatic, as well as cost and spending data for these populations and interventions are then collated. An optimisation analysis of TB spending was conducted in Belarus, using program objectives and constraints defined in collaboration with local stakeholders, which included experts, decision makers, funders and organisations involved in service delivery, support and technical assistance. These analyses show that it is possible to improve health impact by redistributing current TB spending in Belarus. Specifically, shifting funding from inpatient- to outpatient-focused care models, and from mass screening to active case finding strategies, could reduce TB prevalence and mortality by up to 45% and 50%, respectively, by 2035. In addition, an optimised allocation of TB spending could lead to a reduction in drug-resistant TB infections by 40% over this period. This would support progress towards national TB targets without additional financial resources. The case study in Belarus demonstrates how reallocations of spending across existing and new interventions could have a substantial impact on TB outcomes. This highlights the potential for Optima TB and similar modelling tools to support evidence-based priority setting.
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http://dx.doi.org/10.1371/journal.pcbi.1009255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496838PMC
September 2021

Vaccine effectiveness of the first dose of ChAdOx1 nCoV-19 and BNT162b2 against SARS-CoV-2 infection in residents of long-term care facilities in England (VIVALDI): a prospective cohort study.

Lancet Infect Dis 2021 11 23;21(11):1529-1538. Epub 2021 Jun 23.

UCL Institute of Health Informatics, UCL, London, UK. Electronic address:

Background: The effectiveness of SARS-CoV-2 vaccines in older adults living in long-term care facilities is uncertain. We investigated the protective effect of the first dose of the Oxford-AstraZeneca non-replicating viral-vectored vaccine (ChAdOx1 nCoV-19; AZD1222) and the Pfizer-BioNTech mRNA-based vaccine (BNT162b2) in residents of long-term care facilities in terms of PCR-confirmed SARS-CoV-2 infection over time since vaccination.

Methods: The VIVALDI study is a prospective cohort study that commenced recruitment on June 11, 2020, to investigate SARS-CoV-2 transmission, infection outcomes, and immunity in residents and staff in long-term care facilities in England that provide residential or nursing care for adults aged 65 years and older. In this cohort study, we included long-term care facility residents undergoing routine asymptomatic SARS-CoV-2 testing between Dec 8, 2020 (the date the vaccine was first deployed in a long-term care facility), and March 15, 2021, using national testing data linked within the COVID-19 Datastore. Using Cox proportional hazards regression, we estimated the relative hazard of PCR-positive infection at 0-6 days, 7-13 days, 14-20 days, 21-27 days, 28-34 days, 35-48 days, and 49 days and beyond after vaccination, comparing unvaccinated and vaccinated person-time from the same cohort of residents, adjusting for age, sex, previous infection, local SARS-CoV-2 incidence, long-term care facility bed capacity, and clustering by long-term care facility. We also compared mean PCR cycle threshold (Ct) values for positive swabs obtained before and after vaccination. The study is registered with ISRCTN, number 14447421.

Findings: 10 412 care home residents aged 65 years and older from 310 LTCFs were included in this analysis. The median participant age was 86 years (IQR 80-91), 7247 (69·6%) of 10 412 residents were female, and 1155 residents (11·1%) had evidence of previous SARS-CoV-2 infection. 9160 (88·0%) residents received at least one vaccine dose, of whom 6138 (67·0%) received ChAdOx1 and 3022 (33·0%) received BNT162b2. Between Dec 8, 2020, and March 15, 2021, there were 36 352 PCR results in 670 628 person-days, and 1335 PCR-positive infections (713 in unvaccinated residents and 612 in vaccinated residents) were included. Adjusted hazard ratios (HRs) for PCR-positive infection relative to unvaccinated residents declined from 28 days after the first vaccine dose to 0·44 (95% CI 0·24-0·81) at 28-34 days and 0·38 (0·19-0·77) at 35-48 days. Similar effect sizes were seen for ChAdOx1 (adjusted HR 0·32, 95% CI 0·15-0·66) and BNT162b2 (0·35, 0·17-0·71) vaccines at 35-48 days. Mean PCR Ct values were higher for infections that occurred at least 28 days after vaccination than for those occurring before vaccination (31·3 [SD 8·7] in 107 PCR-positive tests vs 26·6 [6·6] in 552 PCR-positive tests; p<0·0001).

Interpretation: Single-dose vaccination with BNT162b2 and ChAdOx1 vaccines provides substantial protection against infection in older adults from 4-7 weeks after vaccination and might reduce SARS-CoV-2 transmission. However, the risk of infection is not eliminated, highlighting the ongoing need for non-pharmaceutical interventions to prevent transmission in long-term care facilities.

Funding: UK Government Department of Health and Social Care.
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http://dx.doi.org/10.1016/S1473-3099(21)00289-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221738PMC
November 2021

Incidence of SARS-CoV-2 infection according to baseline antibody status in staff and residents of 100 long-term care facilities (VIVALDI): a prospective cohort study.

Lancet Healthy Longev 2021 Jun 3;2(6):e362-e370. Epub 2021 Jun 3.

UCL Institute of Health Informatics, University College London, London, UK.

Background: SARS-CoV-2 infection represents a major challenge for long-term care facilities (LTCFs) and many residents and staff are seropositive following persistent outbreaks. We aimed to investigate the association between the SARS-CoV-2 antibody status at baseline and subsequent infection in this population.

Methods: We did a prospective cohort study of SARS-CoV-2 infection in staff (aged <65 years) and residents (aged >65 years) at 100 LTCFs in England between Oct 1, 2020, and Feb 1, 2021. Blood samples were collected between June and November, 2020, at baseline, and 2 and 4 months thereafter and tested for IgG antibodies to SARS-CoV-2 nucleocapsid and spike proteins. PCR testing for SARS-CoV-2 was done weekly in staff and monthly in residents. Cox regression was used to estimate hazard ratios (HRs) of a PCR-positive test by baseline antibody status, adjusted for age and sex, and stratified by LTCF.

Findings: 682 residents from 86 LCTFs and 1429 staff members from 97 LTCFs met study inclusion criteria. At baseline, IgG antibodies to nucleocapsid were detected in 226 (33%) of 682 residents and 408 (29%) of 1429 staff members. 93 (20%) of 456 residents who were antibody-negative at baseline had a PCR-positive test (infection rate 0·054 per month at risk) compared with four (2%) of 226 residents who were antibody-positive at baseline (0·007 per month at risk). 111 (11%) of 1021 staff members who were antibody-negative at baseline had PCR-positive tests (0·042 per month at risk) compared with ten (2%) of 408 staff members who were antibody-positive staff at baseline (0·009 per month at risk). The risk of PCR-positive infection was higher for residents who were antibody-negative at baseline than residents who were antibody-positive at baseline (adjusted HR [aHR] 0·15, 95% CI 0·05-0·44, p=0·0006), and the risk of a PCR-positive infection was also higher for staff who were antibody-negative at baseline compared with staff who were antibody-positive at baseline (aHR 0·39, 0·19-0·82; p=0·012). 12 of 14 reinfected participants had available data on symptoms, and 11 of these participants were symptomatic. Antibody titres to spike and nucleocapsid proteins were comparable in PCR-positive and PCR-negative cases.

Interpretation: The presence of IgG antibodies to nucleocapsid protein was associated with substantially reduced risk of reinfection in staff and residents for up to 10 months after primary infection.

Funding: UK Government Department of Health and Social Care.
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http://dx.doi.org/10.1016/S2666-7568(21)00093-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175048PMC
June 2021

Changes in presentations with features potentially indicating cancer in primary care during the COVID-19 pandemic: a retrospective cohort study.

BMJ Open 2021 05 24;11(5):e050131. Epub 2021 May 24.

Population Health Sciences, University of Bristol Medical School, Bristol, UK.

Objectives: To investigate how the COVID-19 pandemic affected the number of people aged 50+ years presenting to primary care with features that could potentially indicate cancer, and to explore how reporting differed by patient characteristics and in face-to-face vs remote consultations.

Design, Setting And Participants: A retrospective cohort study of general practitioner (GP), nurse and paramedic primary care consultations in 21 practices in South-West England covering 123 947 patients. The models compared potential cancer indicators reported in April-July 2019 with April-July 2020.

Main Outcome Measures: Potential indicators of cancer were identified using code lists for symptoms, signs, test results and diagnoses listed in the National Institute for Health and Care Excellence suspected cancer referral guidance (NG12).

Results: During April-July 2019, 17% of registered patients aged 50+ years reported a potential cancer indicator in a consultation with a GP or nurse. During April-July 2020, this reduced to 11% (incidence rate ratio (IRR) 0.64, 95% CI 0.62 to 0.67, p<0.001). Reductions in potential cancer indicators were stable across age group, sex, ethnicity, index of multiple deprivation quintile and shielding status, but less marked in patients with mental health conditions than without (IRR 0.75, 95% CI 0.72 to 0.79, interaction p<0.001). Proportions of GP consultations with potential indicators of cancer reduced between 2019 and 2020 for face-to-face consultations (IRR 0.84, 95% CI 0.76 to 0.92, p<0.001) and increased for remote consultations (IRR 1.17, 95% CI 1.07 to 1.29, p=0.001), although it remained lower in remote consulting than face-to-face in April-July 2020. This difference was greater for nurse/paramedic consultations (face-to-face: IRR 0.61, 95% CI 0.44 to 0.83, p=0.002; remote: IRR 1.60, 95% CI 1.10 to 2.333, p=0.014).

Conclusion: The number of patients consulting with presentations that could potentially indicate cancer reduced during the first wave of the COVID-19 pandemic. Patients should be encouraged to continue contacting primary care for persistent signs and symptoms, and GPs and nurses should be encouraged to probe patients for further information during remote consulting, in the absence of non-verbal cues.
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http://dx.doi.org/10.1136/bmjopen-2021-050131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154288PMC
May 2021

Study Protocol: Understanding SARS-Cov-2 infection, immunity and its duration in care home residents and staff in England (VIVALDI).

Wellcome Open Res 2020 29;5:232. Epub 2021 Jan 29.

Institute of Health Informatics, University College London, London, NW1 2DA, UK.

Global infection and mortality rates from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are disproportionately high in certain populations, including amongst older people. Care home residents are frequently exposed to infection due to contact with staff and other residents, and are highly susceptible to infection due to their age and co-morbidity. In England, official statistics suggest that at least 25% of all deaths in care home residents since the start of pandemic are linked to coronavirus disease 2019 (COVID-19), but limited testing for SARS-CoV-2 early in the pandemic means estimates of the true burden of disease are lacking. Additionally, little is known about patterns of transmission between care homes, the community and hospitals, or the relationship between infection and immunity in care home staff and residents. The VIVALDI study plans to address these questions. VIVALDI is a prospective cohort study aiming to recruit  6,500 staff and 5000 residents from 105 care homes across England. Successive rounds of testing for infection will be performed over a period of 12 months.  Nasopharyngeal swabs will detect evidence of viral RNA and therefore active infection (accompanied by collection of data on symptoms), whereas blood tests will detect antibodies and evidence of cellular immunity to SARS-CoV-2. Whole genome sequencing of viral isolates to investigate pathways of transmission of infection is planned in collaboration with the COVID-19 Genomics UK Consortium. Qualitative interviews with care home staff will investigate the impact of the pandemic on ways of working and how test results influence infection control practices and behaviours. Data from residents and staff will be linked to national datasets on hospital admissions, antibody and PCR test results, mortality and care home characteristics.  Data generated will support national public health efforts to prevent transmission of COVID-19 and protect care home staff and residents from infection. : ISRCTN14447421 05/06/2020.
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http://dx.doi.org/10.12688/wellcomeopenres.16193.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851710PMC
January 2021

To Adjust or Not to Adjust? When a "Confounder" Is Only Measured After Exposure.

Epidemiology 2021 03;32(2):194-201

MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Advice regarding the analysis of observational studies of exposure effects usually is against adjustment for factors that occur after the exposure, as they may be caused by the exposure (or mediate the effect of exposure on outcome), so potentially leading to collider stratification bias. However, such factors could also be caused by unmeasured confounding factors, in which case adjusting for them will also remove some of the bias due to confounding. We derive expressions for collider stratification bias when conditioning and confounding bias when not conditioning on the mediator, in the presence of unmeasured confounding (assuming that all associations are linear and there are no interactions). Using simulations, we show that generally neither the conditioned nor the unconditioned estimate is unbiased, and the trade-off between them depends on the magnitude of the effect of the exposure that is mediated relative to the effect of the unmeasured confounders and their relations with the mediator. We illustrate the use of the bias expressions via three examples: neuroticism and mortality (adjusting for the mediator appears the least biased option), glycated hemoglobin levels and systolic blood pressure (adjusting gives smaller bias), and literacy in primary school pupils (not adjusting gives smaller bias). Our formulae and simulations can inform quantitative bias analysis as well as analysis strategies for observational studies in which there is a potential for unmeasured confounding.
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http://dx.doi.org/10.1097/EDE.0000000000001312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850592PMC
March 2021

The role of combinatorial health technologies in supporting older people with long-term conditions: Responsibilisation or co-management of healthcare?

Soc Sci Med 2021 01 24;269:113545. Epub 2020 Nov 24.

Centre for Ageing Research, Division of Health Research, Lancaster University, Lancaster, LA1 4AT, UK. Electronic address:

Neoliberalism, austerity and health responsibilisation are increasingly informing policies and practices designed to encourage older patients to take responsibility for the management of their own healthcare. Combined with an ageing population, novel ways to address the increasing healthcare needs of older people have become a priority, with the emergence in recent years of new models of integrated care enhanced by combinatorial health technologies (CHTs). This paper presents qualitative findings from the evaluation of one programme, the Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed, a programme funded by NHS England and conducted in England between 2016 and 2018. Drawing on data from patients, family carers, and staff members involved in the programme, this paper explores the extent to which CHTs, as part of the LCIA Test Bed programme, contributed to health responsibilisation amongst older people with complex health conditions. Through this programme, we find that relationships between patients, family carers and healthcare professionals combined to create a sense of reassurance and shared responsibility for all parties. Our findings suggest the need for a more nuanced approach to responsibilisation and self-management for older people living with complex health conditions. By focusing on co-management - and recognising the potential of CHTs to facilitate this approach - there is potential to increase patient confidence in managing their health condition, reduce carer burden, and enhance clinician satisfaction in their work roles. While neoliberal agendas are focused on self-management and self-responsibility of one's own health care, with technology as a facilitator of this, our findings suggest that the successful use of CHTs for older people with complex health conditions may instead be rooted in co-management. This paper argues that co-management may be a more successful model of care for patients, carers and clinicians.
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http://dx.doi.org/10.1016/j.socscimed.2020.113545DOI Listing
January 2021

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis.

Diabetes Care 2021 02 4;44(2):556-562. Epub 2020 Dec 4.

George Institute for Global Health, University of Oxford, Oxford, U.K.

Objective: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.

Research Design And Methods: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment.

Results: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs.

Conclusions: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.
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http://dx.doi.org/10.2337/dc20-1137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818328PMC
February 2021

Collider bias undermines our understanding of COVID-19 disease risk and severity.

Nat Commun 2020 11 12;11(1):5749. Epub 2020 Nov 12.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.

Numerous observational studies have attempted to identify risk factors for infection with SARS-CoV-2 and COVID-19 disease outcomes. Studies have used datasets sampled from patients admitted to hospital, people tested for active infection, or people who volunteered to participate. Here, we highlight the challenge of interpreting observational evidence from such non-representative samples. Collider bias can induce associations between two or more variables which affect the likelihood of an individual being sampled, distorting associations between these variables in the sample. Analysing UK Biobank data, compared to the wider cohort the participants tested for COVID-19 were highly selected for a range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the mechanisms inducing these problems, and approaches that could help mitigate them. While collider bias should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage.
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http://dx.doi.org/10.1038/s41467-020-19478-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665028PMC
November 2020

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611474PMC
October 2020

Assessment of a causal relationship between body mass index and atopic dermatitis.

J Allergy Clin Immunol 2021 01 17;147(1):400-403. Epub 2020 May 17.

Skin Research Group, School of Medicine, University of Dundee, Dundee, United Kingdom; Department of Dermatology, Ninewells Hospital and Medical School, Dundee, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794861PMC
January 2021

Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis.

PLoS Med 2020 03 23;17(3):e1003062. Epub 2020 Mar 23.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Background: Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD.

Methods And Findings: We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39-73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10-8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10-8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation-higher trait; 95% CI: 1.49-1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25-1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56-1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31-2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57-1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02-1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation-higher HDL cholesterol (OR 0.80; 95% CI: 0.75-0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77-0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components.

Conclusions: These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD.
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http://dx.doi.org/10.1371/journal.pmed.1003062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089422PMC
March 2020

Cost-effectiveness of conditional cash transfers to retain women in the continuum of care during pregnancy, birth and the postnatal period: protocol for an economic evaluation of the Afya trial in Kenya.

BMJ Open 2019 11 6;9(11):e032161. Epub 2019 Nov 6.

Institute for Global Health, University College London, London, UK.

Introduction: A wealth of evidence from a range of country settings indicates that antenatal care, facility delivery and postnatal care can reduce maternal and child mortality and morbidity in high-burden settings. However, the utilisation of these services by pregnant women, particularly in low/middle-income country settings, is well below that recommended by the WHO. The Afya trial aims to assess the impact, cost-effectiveness and scalability of conditional cash transfers to promote increased utilisation of these services in rural Kenya and thus retain women in the continuum of care during pregnancy, birth and the postnatal period. This protocol describes the planned economic evaluation of the Afya trial.

Methods And Analysis: The economic evaluation will be conducted from the provider perspective as a within-trial analysis to evaluate the incremental costs and health outcomes of the cash transfer programme compared with the status quo. Incremental cost-effectiveness ratios will be presented along with a cost-consequence analysis where the incremental costs and all statistically significant outcomes will be listed separately. Sensitivity analyses will be undertaken to explore uncertainty and to ensure that results are robust. A fiscal space assessment will explore the affordability of the intervention. In addition, an analysis of equity impact of the intervention will be conducted.

Ethics And Dissemination: The study has received ethics approval from the Maseno University Ethics Review Committee, REF MSU/DRPI/MUERC/00294/16. The results of the economic evaluation will be disseminated in a peer-reviewed journal and presented at a relevant international conference.

Trial Registration Number: NCT03021070.
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http://dx.doi.org/10.1136/bmjopen-2019-032161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858100PMC
November 2019

Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable.

Sci Rep 2019 06 20;9(1):8986. Epub 2019 Jun 20.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

High systolic blood pressure (SBP) causes cardiovascular disease (CVD) and is associated with mortality from other causes, but conventional multivariably-adjusted results may be confounded. Here we used a son's SBP (>1 million Swedish men) as an instrumental variable for parental SBP and examined associations with parents' cause-specific mortality, avoiding reverse causation. The hazard ratio for CVD mortality per SD (10.80 mmHg) of SBP was 1.49 (95% CI: 1.43, 1.56); SBP was positively associated with coronary heart disease and stroke. SBP was also associated positively with all-cause, diabetes and kidney cancer mortality, and negatively with external causes. Negative associations with respiratory-related mortality were probably confounded by smoking. Hazard ratios for other causes were imprecise or null. Diastolic blood pressure gave similar results to SBP. CVD hazard ratios were intermediate between those from conventional multivariable studies and Mendelian randomization and stronger than those from clinical trials, approximately consistent with an effect of exposure duration on effect sizes. Plots of parental mortality against offspring SBP were approximately linear, supporting calls for lower SBP targets. Results suggest that conventional multivariable analyses of mortality and SBP are not substantially confounded by reverse causation and confirm positive effects of SBP on all-cause, CVD and diabetes mortality.
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http://dx.doi.org/10.1038/s41598-019-45391-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586810PMC
June 2019

Protocol for the cost-consequence and equity impact analyses of a cluster randomised controlled trial comparing three variants of a nutrition-sensitive agricultural extension intervention to improve maternal and child dietary diversity and nutritional status in rural Odisha, India (UPAVAN trial).

Trials 2019 May 27;20(1):287. Epub 2019 May 27.

London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT,, UK.

Background: Undernutrition causes around 3.1 million child deaths annually, around 45% of all child deaths. India has one of the highest proportions of maternal and child undernutrition globally. To accelerate reductions in undernutrition, nutrition-specific interventions need to be coupled with nutrition-sensitive programmes that tackle the underlying causes of undernutrition. This paper describes the planned economic evaluation of the UPAVAN trial, a four-arm, cluster randomised controlled trial that tests the nutritional and agricultural impacts of an innovative agriculture extension platform of women's groups viewing videos on nutrition-sensitive agriculture practices, coupled with a nutrition-specific behaviour-change intervention of videos on nutrition, and a participatory learning and action approach.

Methods: The economic evaluation of the UPAVAN interventions will be conducted from a societal perspective, taking into account all costs incurred by the implementing agency (programme costs), community and health care providers, and participants and their households, and all measurable outcomes associated with the interventions. All direct and indirect costs, including time costs and donated goods, will be estimated. The economic evaluation will take the form of a cost-consequence analysis, comparing incremental costs and incremental changes in the outcomes of the interventions, compared with the status quo. Robustness of the results will be assessed through a series of sensitivity analyses. In addition, an analysis of the equity impact of the interventions will be conducted.

Discussion: Evidence on the cost and cost-effectiveness of nutrition-sensitive agriculture interventions is scarce. This limits understanding of the costs of rolling out or scaling up programs. The findings of this economic evaluation will provide useful information for different multisectoral stakeholders involved in the planning and implementation of nutrition-sensitive agriculture programmes.

Trial Registration: ISRCTN65922679 . Registered on 21 December 2016.
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http://dx.doi.org/10.1186/s13063-019-3388-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537168PMC
May 2019

Conditional cash transfers to retain rural Kenyan women in the continuum of care during pregnancy, birth and the postnatal period: protocol for a cluster randomized controlled trial.

Trials 2019 Mar 1;20(1):152. Epub 2019 Mar 1.

UCL Institute for Global Health, 3rd floor, Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.

Background: Antenatal care (ANC), facility delivery and postnatal care (PNC) are proven to reduce maternal and child mortality and morbidity in high-burden settings. However, few pregnant rural women use these services sufficiently. This study aims to assess the impact, cost-effectiveness and scalability of conditional cash transfers to promote increased contact between pregnant women or women who have recently given birth and the formal healthcare system in Kenya.

Methods: The intervention tested is a conditional cash transfer to women for ANC health visits, a facility birth and PNC visits until their newborn baby reaches 1 year of age. The study is a cluster randomized controlled trial in Siaya County, Kenya. The trial clusters are 48 randomly selected public primary health facilities, 24 of which are in the intervention arm of the study and 24 in the control arm. The unit of randomization is the health facility. A target sample of 7200 study participants comprises pregnant women identified and recruited at their first ANC visit over a 12-month recruitment period and their subsequent newborns. All pregnant women attending one of the selected trial facilities for their first ANC visit during the recruitment period are eligible for the trial and invited to participate. Enrolled mothers are followed up at all health visits during their pregnancy, at facility delivery and for a number of visits after delivery. They are also contacted at three additional time points after enrolling in the study: 5-10days after enrolment, 6 months after the expected delivery date and 12 27 months after birth. If they have not delivered in a facility, there is an additional follow-up 2 wees after the expected due date. The impact of the conditional cash transfers on maternal healthcare services and utilization will be measured by the trial's primary outcomes: the proportion of all eligible ANC visits made during pregnancy, delivery at a health facility, the proportion of all eligible PNC visits attended, the proportion of referrals attended during the pregnancy and the postnatal period, and the proportion of eligible child immunization appointments attended. Secondary outcomes include; health screening and infection control, live birth, maternal and child survival 48 h after delivery, exclusive breastfeeding, post-partum contraceptive use and maternal and newborn morbidity. Data sources for the measurement of outcomes include routine health records, an electronic card-reader system and telephone surveys and focus group discussions. A full economic evaluation will be conducted to assess the cost of delivery and cost effectiveness of the intervention and the benefit incidence and equity impact of trial activities and outcomes.

Discussion: This trial will contribute to evidence on the effectiveness and cost-effectiveness of conditional cash transfers in facilitating health visits and promoting maternal and child health in rural Kenya and in other comparable contexts.

Trial Registration: ClinicalTrials.gov, NCT03021070 . Registered on 13 January 2017.
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http://dx.doi.org/10.1186/s13063-019-3224-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397480PMC
March 2019

Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study.

PLoS Med 2019 01 31;16(1):e1002739. Epub 2019 Jan 31.

Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Background: Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis.

Methods And Findings: Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m2 (95% CI 1.02-1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m2 mean difference (95% CI 1.13-1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03-1.04; P = 1.73 × 10(-60)). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06-1.12) per 1 kg/m2; P = 4.67 × 10(-9)). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m2 change in BMI per doubling odds of psoriasis (-0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied.

Conclusions: Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship.
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http://dx.doi.org/10.1371/journal.pmed.1002739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354959PMC
January 2019

How effective and cost-effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community? An evaluation protocol for an NHS Test Bed in North West England.

BMJ Open 2018 02 28;8(2):e017268. Epub 2018 Feb 28.

Centre for Ageing Research, Division of Health Research, Lancaster University, Lancaster, UK.

Introduction: The Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed is a partnership between the National Health Service in England, industry (led by Philips) and Lancaster University. Through the implementation of a combination of innovative health technologies and practices, it aims to determine the most effective and cost-effective ways of supporting frail older people with long-term conditions to remain well in the community. Among the Test Bed's objectives are to improve patient activation and the ability of older people to self-care at home, reduce healthcare system utilisation, and deliver increased workforce productivity.

Methods And Analysis: Patients aged 55 years and over are recruited to four cohorts defined by their risk of hospital admission, with long-term conditions including chronic obstructive pulmonary disease, dementia, diabetes and heart failure. The programme is determined on an individual basis, with a range of technologies available. The evaluation is adopting a two-phase approach: phase 1 includes a bespoke patient survey and a mass matched control analysis; and phase 2 is using observational interviews with patients, and weekly diaries, action learning meetings and focus groups with members of staff and other key stakeholders. Phase 1 data analysis consists of a statistical evaluation of the effectiveness of the programme. A health economic analysis of its costs and associated cost changes will be undertaken. Phase 2 data will be analysed thematically with the aid of Atlas.ti qualitative software. The evaluation is located within a logic model framework, to consider the processes, management and participation that may have implications for the Test Bed's success.

Ethics And Dissemination: The LCIA Test Bed evaluation has received ethical approval from the Health Research Authority and Lancaster University's Faculty of Health and Medicine Research Ethics Committee. A range of dissemination methods are adopted, including deliberative panels to validate findings and develop outcomes for policy and practice.
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http://dx.doi.org/10.1136/bmjopen-2017-017268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855480PMC
February 2018

Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis.

Clin Psychol Psychother 2018 May 15;25(3):440-445. Epub 2018 Feb 15.

Division of Health Research, School of Health and Medicine, Lancaster University, Lancaster, UK.

We examine associations between client attachment style and therapeutic alliance in a 3-arm randomized controlled trial of brief motivational interviewing and cognitive-behavioural therapy compared with longer term motivational interviewing and cognitive-behavioural therapy or standard care alone. Client self-report measures of attachment style were completed at baseline, and both clients and therapists in the treatment arms of the trial completed alliance measures 1 month into therapy. We found that insecure-anxious attachment was positively associated with therapist-rated alliance, whereas clients with insecure-avoidant attachment were more likely to report poorer bond with therapist. There was no evidence that client attachment significantly predicted clinical or substance misuse outcomes either directly or indirectly via alliance. Nor evidence that the length of therapy offered interacted with attachment to predict alliance.
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http://dx.doi.org/10.1002/cpp.2178DOI Listing
May 2018

Reading comprehension difficulties in children with rolandic epilepsy.

Dev Med Child Neurol 2018 03 14;60(3):275-282. Epub 2017 Dec 14.

Department of Psychology, Lancaster University, Lancaster, UK.

Aim: Difficulties in reading comprehension can arise from either word reading or listening comprehension difficulties, or a combination of the two. We sought to determine whether children with rolandic epilepsy had poor reading comprehension relative to typically developing comparison children, and whether such difficulties were associated with word reading and/or general language comprehension difficulties.

Method: In this cross-sectional study, children with rolandic epilepsy (n=25; 16 males, 9 females; mean age 9y 1mo, SD 1y 7mo) and a comparison group (n=39; 25 males, 14 females; mean age 9y 1mo, SD 1y 3mo) completed assessments of reading comprehension, listening comprehension, word/non-word reading, speech articulation, and Non-verbal IQ.

Results: Reading comprehension and word reading were worse in children with rolandic epilepsy (F =6.89, p=0.011, ηp2=0.10 and F =6.84, p=0.011, ηp2=0.10 respectively), with listening comprehension being marginal (F =3.81, p=0.055, ηp2=0.06). Word reading and listening comprehension made large and independent contributions to reading comprehension, explaining 70% of the variance.

Interpretation: Children with rolandic epilepsy may be at risk of reading comprehension difficulties. Thorough assessment of individual children is required to ascertain whether the difficulties lie with decoding text, or with general comprehension skills, or both.

What This Paper Adds: Children with rolandic epilepsy may be at risk of poor reading comprehension. This was related to poor word reading, poor listening comprehension, or both. Reading comprehension interventions should be tailored to the profile of difficulties.
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http://dx.doi.org/10.1111/dmcn.13628DOI Listing
March 2018

Instrumental variable methods for a binary outcome were used to informatively address noncompliance in a randomized trial in surgery.

J Clin Epidemiol 2018 04 20;96:126-132. Epub 2017 Nov 20.

Centre for Biostatistics, School of Health Sciences, Manchester Academic Health Science Centre, The University of Manchester, Jean McFarlane Building, Oxford Road, Manchester, M139PL, UK.

Objectives: Randomization can be used as an instrumental variable (IV) to account for unmeasured confounding when seeking to assess the impact of noncompliance with treatment allocation in a randomized trial. We present and compare different methods to calculate the treatment effect on a binary outcome as a rate ratio in a randomized surgical trial.

Study Design And Setting: The effectiveness of peeling versus not peeling the internal limiting membrane of the retina as part of the surgery for a full thickness macular hole. We compared the IV-based estimates (nonparametric causal bound and two-stage residual inclusion approach [2SRI]) with standard treatment effect measures (intention to treat, per protocol and treatment received [TR]). Compliance was defined in two ways (initial and up to the time point of interest). Poisson regression was used for the model-based approaches with robust standard errors to calculate the risk ratio (RR) with 95% confidence intervals.

Results: Results were similar for 1-month macular hole status across methods. For 3- and 6-month macular hole status, nonparametric causal bounds provided a narrower range of uncertainty than other methods, though still had substantial imprecision. For 3-month macular hole status, the TR estimate was substantially different from the other point estimates.

Conclusion: Nonparametric causal bound approaches are a useful addition to an IV estimation approach, which tend to have large levels of uncertainty. Methods which allow RRs to be calculated when addressing noncompliance in randomized trials exist and may be superior to standard estimates. Further research is needed to explore the properties of different IV methods in a broad range of randomized controlled trial scenarios.
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http://dx.doi.org/10.1016/j.jclinepi.2017.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862096PMC
April 2018

Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies.

Am J Epidemiol 2017 Nov;186(9):1104-1114

Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two-stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroscedasticity-robust standard errors for these estimates. We compared several different forms of the standard error for linear and logistic TSRI estimates in simulations and in real-data examples. Among others, we consider standard errors modified from the approach of Newey (1987), Terza (2016), and bootstrapping. In our simulations Newey, Terza, bootstrap, and corrected 2-stage least squares (in the linear case) standard errors gave the best results in terms of coverage and type I error. In the real-data examples, the Newey standard errors were 0.5% and 2% larger than the unadjusted standard errors for the linear and logistic TSRI estimators, respectively. We show that TSRI estimators with modified standard errors have correct type I error under the null. Researchers should report TSRI estimates with modified standard errors instead of reporting unadjusted or heteroscedasticity-robust standard errors.
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http://dx.doi.org/10.1093/aje/kwx175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860380PMC
November 2017

Education and coronary heart disease: mendelian randomisation study.

BMJ 2017 Aug 30;358:j3542. Epub 2017 Aug 30.

Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

 To determine whether educational attainment is a causal risk factor in the development of coronary heart disease. Mendelian randomisation study, using genetic data as proxies for education to minimise confounding. The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors. The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin. A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education. Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D). Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile. This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594424PMC
http://dx.doi.org/10.1136/bmj.j3542DOI Listing
August 2017

Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis.

Circulation 2017 Jun 12;135(24):2373-2388. Epub 2017 May 12.

From Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, United Kingdom (C.E.D., G.F., D.P.-M., A.D.H., J.P.C.); Department of Mathematics and Statistics, Lancaster University, United Kingdom (T.M.P.); UCLGenetics Institute, University College London, United Kingdom (J.W.); Applied Statistical Methods in Medical Research Group, Universidad Catolica de San Antonio de Murcia, Spain (D.P.-M.); Social Genetic & Developmental Psychiatry, King's College London, United Kingdom (D.Z.); Institute of Cardiovascular Science, University College London, United Kingdom (J.E.L.E., T.S., A.D.H., S.E.H.); MRC Unit for Lifelong Health & Ageing at UCL, London, United Kingdom (A.W., D.K.); Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (H.R.W., M.J.C., P.B.M.); NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (H.R.W., M.J.C., P.B.M.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (S.M., J.F.P.); Department of Cardiology, Leiden University Medical Center, The Netherlands (S.T., W.J.); South Australian Health and Medical Research Institute, Adelaide (M.M., E.H.); EMBL Australia, Adelaide (M.M.); School of Social and Community Medicine, University of Bristol, United Kingdom (R.W.M., T.R.G., Y.B.-S., D.A.L., G.D.S.); Centre for Clinical Pharmacology, University College London, United Kingdom (R.S.); Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom (M.K.); Centre for Population Health Research, School of Health Sciences and Sansom Institute, University of South Australia, Adelaide (E.H., A.Z.); Population, Policy & Practice, UCL Great Ormond Street Institute of Child Health, London, United Kingdom (E.H., C.P.); Department of Primary Care & Population Health, University College London, Royal Free Campus, United Kingdom (B.J.J.); MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom (T.R.G., D.A.L., G.D.S.); Department of Women's Cancer, Institute for Women's Health, UCL, London, United Kingdom (A.G.-M., A.R., U.M.); Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands (R.d.M., D.O.M.-K.); Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, The Netherlands (R.N., S.T.); Interuniversity Cardiology Institute Netherlands, Utrecht (W.J.); Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville (B.B.W.); Department of Public Health and Primary Care, Leiden University Medical Center, The Netherlands (D.O.M.-K.); BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, United Kingdom (N.S.); Department of Epidemiology and Public Health, University College London, United Kingdom (M.K.); Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom (F.D.); Department of Health Sciences, University of Leicester, United Kingdom (F.D.); Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute Building, University of Oxford, United Kingdom (M.V.H.); Medical Research Council Population Health Research Unit at the University of Oxford, United Kingdom (M.V.H.); and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals, United Kingdom (M.V.H.).

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease.

Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits.

Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD).

Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515354PMC
June 2017
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