Prioritising cardiovascular disease risk assessment to high risk individuals based on primary care records.

OBJECTIVE: To provide quantitative evidence for systematically prioritising individuals for full formal cardiovascular disease (CVD) risk assessment using primary care records with a novel tool (eHEART) with age- and sex- specific risk thresholds. METHODS AND ANALYSIS: eHEART was derived using landmark Cox models for incident CVD with repeated measures of conventional CVD risk predictors in 1,642,498 individuals from the Clinical Practice Research Datalink. Using 119,137 individuals from UK Biobank, we modelled the implications of initiating guideline-recommended statin therapy using eHEART with age- and sex-specific prioritisation thresholds corresponding to 5% false negative rates to prioritise adults aged 40-69 years in a population in England for invitation to a formal CVD risk assessment. RESULTS: Formal CVD risk assessment on all adults would identify 76% and 49% of future CVD events amongst men and women respectively, and 93 (95% CI: 90, 95) men and 279 (95% CI: 259, 297) women would need to be screened (NNS) to prevent one CVD event. In contrast, if eHEART was first used to prioritise individuals for formal CVD risk assessment, we would identify 73% and 47% of future events amongst men and women respectively, and a NNS of 75 (95% CI: 72, 77) men and 162 (95% CI: 150, 172) women. Replacing the age- and sex-specific prioritisation thresholds with a 10% threshold identify around 10% less events. CONCLUSIONS: The use of prioritisation tools with age- and sex-specific thresholds could lead to more efficient CVD assessment programmes with only small reductions in effectiveness at preventing new CVD events.

Using Polygenic Risk Scores for Prioritizing Individuals at Greatest Need of a Cardiovascular Disease Risk Assessment.

Background The aim of this study was to provide quantitative evidence of the use of polygenic risk scores for systematically identifying individuals for invitation for full formal cardiovascular disease (CVD) risk assessment. Methods and Results A total of 108 685 participants aged 40 to 69 years, with measured biomarkers, linked primary care records, and genetic data in UK Biobank were used for model derivation and population health modeling. Prioritization tools using age, polygenic risk scores for coronary artery disease and stroke, and conventional risk factors for CVD available within longitudinal primary care records were derived using sex-specific Cox models. We modeled the implications of initiating guideline-recommended statin therapy after prioritizing individuals for invitation to a formal CVD risk assessment. If primary care records were used to prioritize individuals for formal risk assessment using age- and sex-specific thresholds corresponding to 5% false-negative rates, then the numbers of men and women needed to be screened to prevent 1 CVD event are 149 and 280, respectively. In contrast, adding polygenic risk scores to both prioritization and formal assessments, and selecting thresholds to capture the same number of events, resulted in a number needed to screen of 116 for men and 180 for women. Conclusions Using both polygenic risk scores and primary care records to prioritize individuals at highest risk of a CVD event for a formal CVD risk assessment can efficiently prioritize those who need interventions the most than using primary care records alone. This could lead to better allocation of resources by reducing the number of risk assessments in primary care while still preventing the same number of CVD events.

Incremental value of risk factor variability for cardiovascular risk prediction in individuals with type 2 diabetes: results from UK primary care electronic health records.

BACKGROUND: Cardiovascular disease (CVD) risk prediction models for individuals with type 2 diabetes are important tools to guide intensification of interventions for CVD prevention. We aimed to assess the added value of incorporating risk factors variability in CVD risk prediction for people with type 2 diabetes. METHODS: We used electronic health records (EHRs) data from 83 910 adults with type 2 diabetes but without pre-existing CVD from the UK Clinical Practice Research Datalink for 2004-2017. Using a landmark-modelling approach, we developed and validated sex-specific Cox models, incorporating conventional predictors and trajectories plus variability of systolic blood pressure (SBP), total and high-density lipoprotein (HDL) cholesterol, and glycated haemoglobin (HbA1c). Such models were compared against simpler models using single last observed values or means. RESULTS: The standard deviations (SDs) of SBP, HDL cholesterol and HbA1c were associated with higher CVD risk (P < 0.05). Models incorporating trajectories and variability of continuous predictors demonstrated improvement in risk discrimination (C-index = 0.659, 95% CI: 0.654-0.663) as compared with using last observed values (C-index = 0.651, 95% CI: 0.646-0.656) or means (C-index = 0.650, 95% CI: 0.645-0.655). Inclusion of SDs of SBP yielded the greatest improvement in discrimination (C-index increase = 0.005, 95% CI: 0.004-0.007) in comparison to incorporating SDs of total cholesterol (C-index increase = 0.002, 95% CI: 0.000-0.003), HbA1c (C-index increase = 0.002, 95% CI: 0.000-0.003) or HDL cholesterol (C-index increase= 0.003, 95% CI: 0.002-0.005). CONCLUSION: Incorporating variability of predictors from EHRs provides a modest improvement in CVD risk discrimination for individuals with type 2 diabetes. Given that repeat measures are readily available in EHRs especially for regularly monitored patients with diabetes, this improvement could easily be achieved.

Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses.

BACKGROUND: Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD. METHODS AND FINDINGS: Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703-0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009-0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40-75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation. CONCLUSIONS: Our results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale.

Risk assessment for hospital admission in patients with COPD; a multi-centre UK prospective observational study.

In chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD requiring hospital admission is associated with mortality and healthcare costs. The ERICA study assessed multiple clinical measures in people with COPD, including the short physical performance battery (SPPB), a simple test of physical function with 3 components (gait speed, balance and sit-to-stand). We tested the hypothesis that SPPB score would relate to risk of hospital admissions and length of hospital stay. Data were analysed from 714 of the total 729 participants (434 men and 280 women) with COPD. Data from this prospective observational longitudinal study were obtained from 4 secondary and 1 tertiary centres from England, Scotland, and Wales. The main outcome measures were to estimate the risk of hospitalisation with acute exacerbation of COPD (AECOPD and length of hospital stay derived from hospital episode statistics (HES). In total, 291 of 714 individuals experienced 762 hospitalised AECOPD during five-year follow up. Poorer performance of SPPB was associated with both higher rate (IRR 1.08 per 1 point decrease, 95% CI 1.01 to 1.14) and increased length of stay (IRR 1.18 per 1 point decrease, 95% CI 1.10 to 1.27) for hospitalised AECOPD. For the individual sit-to-stand component of the SPPB, the association was even stronger (IRR 1.14, 95% CI 1.02 to 1.26 for rate and IRR 1.32, 95% CI 1.16 to 1.49 for length of stay for hospitalised AECOPD). The SPPB, and in particular the sit-to-stand component can both evaluate the risk of H-AECOPD and length of hospital stay in COPD. The SPPB can aid in clinical decision making and when prioritising healthcare resources.

Design of the HPTN 065 (TLC-Plus) study: A study to evaluate the feasibility of an enhanced test, link-to-care, plus treat approach for HIV prevention in the United States.

Background/Aims HIV continues to be a major public health threat in the United States, and mathematical modeling has demonstrated that the universal effective use of antiretroviral therapy among all HIV-positive individuals (i.e. the "test and treat" approach) has the potential to control HIV. However, to accomplish this, all the steps that define the HIV care continuum must be achieved at high levels, including HIV testing and diagnosis, linkage to and retention in clinical care, antiretroviral medication initiation, and adherence to achieve and maintain viral suppression. The HPTN 065 (Test, Link-to-Care Plus Treat [TLC-Plus]) study was designed to determine the feasibility of the "test and treat" approach in the United States. Methods HPTN 065 was conducted in two intervention communities, Bronx, NY, and Washington, DC, along with four non-intervention communities, Chicago, IL; Houston, TX; Miami, FL; and Philadelphia, PA. The study consisted of five components: (1) exploring the feasibility of expanded HIV testing via social mobilization and the universal offer of testing in hospital settings, (2) evaluating the effectiveness of financial incentives to increase linkage to care, (3) evaluating the effectiveness of financial incentives to increase viral suppression, (4) evaluating the effectiveness of a computer-delivered intervention to decrease risk behavior in HIV-positive patients in healthcare settings, and (5) administering provider and patient surveys to assess knowledge and attitudes regarding the use of antiretroviral therapy for prevention and the use of financial incentives to improve health outcomes. The study used observational cohorts, cluster and individual randomization, and made novel use of the existing national HIV surveillance data infrastructure. All components were developed with input from a community advisory board, and pragmatic methods were used to implement and assess the outcomes for each study component. Results A total of 76 sites in Washington, DC, and the Bronx, NY, participated in the study: 37 HIV test sites, including 16 hospitals, and 39 HIV care sites. Between September 2010 and December 2014, all study components were successfully implemented at these sites and resulted in valid outcomes. Our pragmatic approach to the study design, implementation, and the assessment of study outcomes allowed the study to be conducted within established programmatic structures and processes. In addition, it was successfully layered on the ongoing standard of care and existing data infrastructure without disrupting health services. Conclusion The HPTN 065 study demonstrated the feasibility of implementing and evaluating a multi-component "test and treat" trial that included a large number of community sites and involved pragmatic approaches to study implementation and evaluation.

Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

Disparities in achieving and sustaining viral suppression among a large cohort of HIV-infected persons in care - Washington, DC.

One goal of the HIV care continuum is achieving viral suppression (VS), yet disparities in suppression exist among subpopulations of HIV-infected persons. We sought to identify disparities in both the ability to achieve and sustain VS among an urban cohort of HIV-infected persons in care. Data from HIV-infected persons enrolled at the 13 DC Cohort study clinical sites between January 2011 and June 2014 were analyzed. Univariate and multivariate logistic regression were conducted to identify factors associated with achieving VS (viral load < 200 copies/ml) at least once, and Kaplan-Meier (KM) curves and Cox proportional hazards models were used to identify factors associated with sustaining VS and time to virologic failure (VL ≥ 200 copies/ml after achievement of VS). Among the 4311 participants, 95.4% were either virally suppressed at study enrollment or able to achieve VS during the follow-up period. In multivariate analyses, achieving VS was significantly associated with age (aOR: 1.04; 95%CI: 1.03-1.06 per five-year increase) and having a higher CD4 (aOR: 1.05, 95% CI 1.04-1.06 per 100 cells/mm(3)). Patients infected through perinatal transmission were less likely to achieve VS compared to MSM patients (aOR: 0.63, 95% CI 0.51-0.79). Once achieved, most participants (74.4%) sustained VS during follow-up. Blacks and perinatally infected persons were less likely to have sustained VS in KM survival analysis (log rank chi-square p ≤ .001 for both) compared to other races and risk groups. Earlier time to failure was observed among females, Blacks, publically insured, perinatally infected, those with longer standing HIV infection, and those with diagnoses of mental health issues or depression. Among this HIV-infected cohort, most people achieved and maintained VS; however, disparities exist with regard to patient age, race, HIV transmission risk, and co-morbid conditions. Identifying populations with disparate outcomes allows for appropriate targeting of resources to improve outcomes along the care continuum.

Did PEPFAR investments result in health system strengthening? A retrospective longitudinal study measuring non-HIV health service utilization at the district level.

OBJECTIVES : PEPFAR's initial rapid scale-up approach was largely a vertical effort focused fairly exclusively on AIDS. The purpose of our research was to identify spill-over health system effects, if any, of investments intended to stem the HIV epidemic over a 6-year period with evidence from Uganda. The test of whether there were health system expansions (aside from direct HIV programming) was evidence of increases in utilization of non-HIV services-such as outpatient visits, in-facility births or immunizations-that could be associated with varying levels of PEPFAR investments at the district level. METHODS : Uganda's Health Management Information System article-based records were available from mid-2005 onwards. We visited all 112 District Health offices to collect routine monthly reports (which contain data aggregated from monthly facility reports) and annual reports (which contain data aggregated from annual facility reports). Counts of individuals on anti-retroviral therapy (ART) at year-end served as our primary predictor variable. We grouped district-months into tertiles of high, medium or low PEPFAR investment based on their total reported number of patients on ART at the end of the year. We generated incidence-rate ratios, interpreted as the relative rate of the outcome measure in relation to the lowest investment PEPFAR tertile, holding constant control variables in the model. RESULTS : We found PEPFAR investment overall was associated with small declines in service volumes in several key areas of non-HIV care (outpatient care for young children, TB tests and in-facility deliveries), after adjusting for sanitation, elementary education and HIV prevalence. For example, districts with medium and high ART investment had 11% fewer outpatient visits for children aged 4 and younger compared with low investment districts, incidence rate ratio (IRR) of 0.89 for high investment compared with low (95% CI, 0.85-0.94) and IRR of 0.93 for medium compared with low (0.90-0.96). Similarly, 22% fewer TB sputum tests were performed in high investment districts compared with low investment, [IRR 0.78 (0.72-0.85)] and 13% fewer in medium compared with low, [IRR 0.88 (0.83-0.94)]. Districts with medium and high ART investment had 5% fewer in-facility deliveries compared with low investment districts [IRR 0.95 for high compared with low, (91-1.00) and 0.96 for medium compared with low (0.93-0.99)]. Although not statistically significant, the rate of maternal deaths in high investment district-months was 13% lower than observed in low investment districts. CONCLUSIONS : This study sought to understand whether PEPFAR, as a vertical programme, may have had a spill-over effect on the health system generally, as measured by utilization. Our conclusion is that it did not, at least not in Uganda.

The estimation and use of predictions for the assessment of model performance using large samples with multiply imputed data.

Multiple imputation can be used as a tool in the process of constructing prediction models in medical and epidemiological studies with missing covariate values. Such models can be used to make predictions for model performance assessment, but the task is made more complicated by the multiple imputation structure. We summarize various predictions constructed from covariates, including multiply imputed covariates, and either the set of imputation-specific prediction model coefficients or the pooled prediction model coefficients. We further describe approaches for using the predictions to assess model performance. We distinguish between ideal model performance and pragmatic model performance, where the former refers to the model's performance in an ideal clinical setting where all individuals have fully observed predictors and the latter refers to the model's performance in a real-world clinical setting where some individuals have missing predictors. The approaches are compared through an extensive simulation study based on the UK700 trial. We determine that measures of ideal model performance can be estimated within imputed datasets and subsequently pooled to give an overall measure of model performance. Alternative methods to evaluate pragmatic model performance are required and we propose constructing predictions either from a second set of covariate imputations which make no use of observed outcomes, or from a set of partial prediction models constructed for each potential observed pattern of covariate. Pragmatic model performance is generally lower than ideal model performance. We focus on model performance within the derivation data, but describe how to extend all the methods to a validation dataset.

Burden of paediatric pyoderma and scabies in North West Queensland.

AIM: The study aims to assess the health burden of children admitted with 'scabies' to Mt Isa Hospital, the referral centre for North West Queensland, from 2006 to 2010. METHODS: This is a retrospective chart audit of admissions of children with 'scabies' including age, sex, date, residence, Indigenous status, result of skin swabs and length of stay, and the number of admissions with acute rheumatic fever (ARF) and acute post-streptococcal glomerulo-nephritis (APSGN) in that period. Financial burden was estimated from daily bed costs and transportation. RESULTS: There were 113 admissions with mean age of 23/12: 11% were <2/12 and mean stay was 4.5 days. 19 were admitted twice, 5 thrice and 2 four times. 7 individuals accounted for 25% of admissions. 'Scabies' accounted for 10.1% of medical admissions <5 years of age. Admissions increased from 10 in 2005 to 39 in 2010. The minimum cost per admission was $9584.07. Seventy-one per cent of swabs grew Group A streptococcus, all sensitive to penicillin. Sixty-three per cent of these were accompanied by Staphylococcus aureus, which was the sole organism in 18%. Sixty-four per cent of S. aureus were methicillin resistant. There were 29 admissions for ARF and 23 with APSGN. All children with 'scabies' and ARF and all but three with APSGN were Indigenous. CONCLUSION: Pyoderma and scabies are major health burdens in North West Queensland, requiring organised community-based prevention. The number of repeat admissions emphasises the futility of individual treatment.

Trends in socioeconomic inequalities in risk of sudden infant death syndrome, other causes of infant mortality, and stillbirth in Scotland: population based study.

OBJECTIVES: To compare changes in inequalities in sudden infant death syndrome with other causes of infant mortality and stillbirth in Scotland, 1985-2008. DESIGN: Retrospective cohort study. SETTING: Scotland 1985-2008, analysed by four epochs of six years. PARTICIPANTS: Singleton births of infants with birth weight >500 g born at 28-43 weeks' gestation. MAIN OUTCOME MEASURES: Sudden infant death syndrome, other causes of postneonatal infant death, neonatal death, and stillbirth. Odds ratios expressed as the association across the range of seven categories of Carstairs deprivation score. RESULTS: The association between deprivation and the risk of all cause stillbirth and infant death varied between the four epochs (P=0.04). This was wholly explained by variation in the risk of sudden infant death syndrome (P<0.001 for interaction). Among women living in areas of low deprivation, there was a sharp decline in the rate of sudden infant death syndrome from 1990 to 1993. Among women living in areas of high deprivation, there was a slower decline in sudden infant death syndrome rates between 1992 and 2004. Consequently, the odds ratio for the association between socioeconomic deprivation and sudden infant death syndrome increased from 2.04 (95% confidence interval 1.53 to 2.72) in 1985-90, to 7.52 (4.62 to 12.25) in 1991-6, and 9.50 (5.46 to 16.53) in 1997-2002 but fell to 1.78 (0.87 to 3.65) in 2002-8. The interaction remained significant after adjustment for maternal characteristics. CONCLUSION: The rate of sudden infant death syndrome declined throughout Scotland in the early 1990s. The decline had a later onset and was slower among women living in areas of high deprivation, probably because of slower uptake of recommended changes in infant sleeping position. The effect was to create a strong independent association between deprivation and sudden infant death syndrome where one did not exist before.

A framework for quantifying net benefits of alternative prognostic models.

New prognostic models are traditionally evaluated using measures of discrimination and risk reclassification, but these do not take full account of the clinical and health economic context. We propose a framework for comparing prognostic models by quantifying the public health impact (net benefit) of the treatment decisions they support, assuming a set of predetermined clinical treatment guidelines. The change in net benefit is more clinically interpretable than changes in traditional measures and can be used in full health economic evaluations of prognostic models used for screening and allocating risk reduction interventions. We extend previous work in this area by quantifying net benefits in life years, thus linking prognostic performance to health economic measures; by taking full account of the occurrence of events over time; and by considering estimation and cross-validation in a multiple-study setting. The method is illustrated in the context of cardiovascular disease risk prediction using an individual participant data meta-analysis. We estimate the number of cardiovascular-disease-free life years gained when statin treatment is allocated based on a risk prediction model with five established risk factors instead of a model with just age, gender and region. We explore methodological issues associated with the multistudy design and show that cost-effectiveness comparisons based on the proposed methodology are robust against a range of modelling assumptions, including adjusting for competing risks.

Legal aspects of laboratory medicine and pathology for residents and fellows: a curriculum for pathology training programs.

CONTEXT: Preparing residents and fellows to manage laboratories and pathology practices increasingly requires awareness of the law and a framework within which to manage legal risk in dealing with compliance, malpractice, and human resources issues. OBJECTIVES: To describe a curriculum for pathology and laboratory medicine residents and fellows that highlights activities most likely to result in adverse legal outcomes and to help trainees understand when the services of an attorney may be required. DESIGN: The 3-hour course evolved as part of a comprehensive leadership and management curriculum designed to help meet systems-based practice and professionalism requirements. Didactic lectures and interactive case scenarios were presented, and participants then evaluated the course content and speakers on a 5-point scale (5 = high). Short-term knowledge accumulation was assessed by comparison of performance on the laboratory administration section of the Resident In-Service Examination between junior residents who had not taken the course and senior residents who did take the course. RESULTS: The course was evaluated by 72 trainees during a 5-year period (2004-2008); the mean overall rating was 4.6 (range, 3.5-5.0). Senior residents (n = 37) had a mean (SD) score on the Resident In-Service Examination laboratory administration section of 521 (67) for 2004 through 2008. Junior residents (n = 51), who had not yet completed the course, scored 470 (70) (P < .001) for the same period. CONCLUSIONS: This curriculum met the needs of professionals entering careers in laboratory medicine and pathology and can be modified for other pathology and laboratory medicine training programs.

Allowing for uncertainty due to missing data in meta-analysis--part 2: hierarchical models.

We propose a hierarchical model for the analysis of data from several randomized trials where some outcomes are missing. The degree of departure from a missing-at-random assumption in each arm of each trial is expressed by an informative missing odds ratio (IMOR). We require a realistic prior for the IMORs, including an assessment of the prior correlation between IMORs in different arms and in different trials. The model is fitted by Monte Carlo Markov Chain techniques. By applying the method in three different data sets, we show that it is possible to appropriately capture the extra uncertainty due to missing data, and we discuss in what circumstances it is possible to learn about the IMOR.

The impact of hyperemesis gravidarum on maternal role assumption.

OBJECTIVES: To describe what it is like to have hyperemesis gravidarum and explore its impact on the assumption of the maternal role during the perinatal period. DESIGN: Qualitative descriptive design. PARTICIPANTS: Eight women who had been diagnosed with hyperemesis gravidarum were recruited through private prenatal clinics using a snowball technique. Participants were interviewed about their experiences with hyperemesis gravidarum in their homes or other suitable sites selected by them. MAIN OUTCOME MEASURES: Transcribed interviews were analyzed using grounded theory methodology. A core category and subcategories were determined. RESULTS: Hyperemesis gravidarum is a disorder that alters the usual response to pregnancy and birth. Participants in this study described it as so debilitating that they had little concern for anything else, including the fetus. After symptoms subsided, the participants reported that they were able to regain control over their lives and made an effort to make up for lost time in becoming attached to the baby. CONCLUSION: Women suffering from hyperemesis gravidarum may not benefit from the usual prenatal education efforts. Additional support following delivery may be needed as the woman attaches to her infant and learns to provide care.

Comparison of imputation and modelling methods in the analysis of a physical activity trial with missing outcomes.

BACKGROUND: Longitudinal studies almost always have some individuals with missing outcomes. Inappropriate handling of the missing data in the analysis can result in misleading conclusions. Here we review a wide range of methods to handle missing outcomes in single and repeated measures data and discuss which methods are most appropriate. METHODS: Using data from a randomized controlled trial to compare two interventions for increasing physical activity, we compare complete-case analysis; ad hoc imputation techniques such as last observation carried forward and worst-case; model-based imputation; longitudinal models with random effects; and recently proposed joint models for repeated measures data and non-ignorable dropout. RESULTS: Estimated intervention effects from ad hoc imputation methods vary widely. Standard multiple imputation and longitudinal modelling agree closely, as they should. Modifying the modelling method to allow for non-ignorable dropout had little effect on estimated intervention effects, but imputing using a common imputation model in both groups gave more conservative results. CONCLUSIONS: Results from ad hoc imputation methods should be avoided in favour of methods with more plausible assumptions although they may be computationally more complex. Although standard multiple imputation methods and longitudinal modelling methods are equivalent for estimating the treatment effect, the two approaches suggest different ways of relaxing the assumptions, and the choice between them depends on contextual knowledge.