Validity of acute cardiovascular outcome diagnoses in European electronic health records: a systematic review protocol

INTRODUCTION: Cardiovascular diseases (CVDs) are among the leading causes of death globally. Electronic health records (EHRs) provide a rich data source for research on CVD risk factors, treatments and outcomes. Researchers must be confident in the validity of diagnoses in EHRs, particularly when diagnosis definitions and use of EHRs change over time. Our systematic review provides an up-to-date appraisal of the validity of stroke, acute coronary syndrome (ACS) and heart failure (HF) diagnoses in European primary and secondary care EHRs. METHODS AND ANALYSIS: We will systematically review the published and grey literature to identify studies validating diagnoses of stroke, ACS and HF in European EHRs. MEDLINE, EMBASE, SCOPUS, Web of Science, Cochrane Library, OpenGrey and EThOS will be searched from the dates of inception to April 2019. A prespecified search strategy of subject headings and free-text terms in the title and abstract will be used. Two reviewers will independently screen titles and abstracts to identify eligible studies, followed by full-text review. We require studies to compare clinical codes with a suitable reference standard. Additionally, at least one validation measure (sensitivity, specificity, positive predictive value or negative predictive value) or raw data, for the calculation of a validation measure, is necessary. We will then extract data from the eligible studies using standardised tables and assess risk of bias in individual studies using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Data will be synthesised into a narrative format and heterogeneity assessed. Meta-analysis will be considered when a sufficient number of homogeneous studies are available. The overall quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation tool. ETHICS AND DISSEMINATION: This is a systematic review, so it does not require ethical approval. Our results will be submitted for peer-review publication. PROSPERO REGISTRATION NUMBER: CRD42019123898

Validity of Acute Cardiovascular Outcome Diagnoses Recorded in European Electronic Health Records: A Systematic Review.

Background: Electronic health records are widely used in cardiovascular disease research. We appraised the validity of stroke, acute coronary syndrome and heart failure diagnoses in studies conducted using European electronic health records. Methods: Using a prespecified strategy, we systematically searched seven databases from dates of inception to April 2019. Two reviewers independently completed study selection, followed by partial parallel data extraction and risk of bias assessment. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value estimates were narratively synthesized and heterogeneity between sensitivity and PPV estimates were assessed using I2. Results: We identified 81 studies, of which 20 validated heart failure diagnoses, 31 validated acute coronary syndrome diagnoses with 29 specifically recording estimates for myocardial infarction, and 41 validated stroke diagnoses. Few studies reported specificity or negative predictive value estimates. Sensitivity was ≤66% in all but one heart failure study, ≥80% for 91% of myocardial infarction studies, and ≥70% for 73% of stroke studies. PPV was ≥80% in 74% of heart failure, 88% of myocardial infarction, and 70% of stroke studies. PPV by stroke subtype was variable, at ≥80% for 80% of ischaemic stroke but only 44% of haemorrhagic stroke. There was considerable heterogeneity (I2 >75%) between sensitivity and PPV estimates for all diagnoses. Conclusion: Overall, European electronic health record stroke, acute coronary syndrome and heart failure diagnoses are accurate for use in research, although validity estimates for heart failure and individual stroke subtypes were lower. Where possible, researchers should validate data before use or carefully interpret the results of previous validation studies for their own study purposes

The bidirectional longitudinal association between depressive symptoms and HbA 1c : a systematic review and meta‐analysis

Aim To investigate whether there is a bidirectional longitudinal association of depression with HbA1c. Methods We conducted a systematic literature search in PubMed, PsycINFO, CINAHL and EMBASE for observational, longitudinal studies published from January 2000 to September 2020, assessing the association between depression and HbA1c in adults. We assessed study quality with the Newcastle-Ottawa-Scale. Pooled effect estimates were reported as partial correlation coefficients (rp) or odds ratios (OR). Results We retrieved 1,642 studies; 26 studies were included in the systematic review and eleven in the meta-analysis. Most studies (16/26) focused on type 2 diabetes. Study quality was rated as good (n=19), fair (n=2) and poor (n=5). Of the meta-analysed studies, six investigated the longitudinal association between self-reported depressive symptoms and HbA1c and five the reverse longitudinal association, with a combined sample size of n=48,793 and a mean follow-up of 2 years. Higher levels of baseline depressive symptoms were associated with subsequent higher levels of HbA1c (partial r=0.07;[95%CI0.03,0.12]; I238%). Higher baseline HbA1c values were also associated with 18% increased risk of (probable) depression (OR=1.18;[95%CI1.12,1.25]; I20.0%). Conclusions Our findings support a bidirectional longitudinal association between depressive symptoms and HbA1c. However, the observed effect sizes were small and future research in large-scale longitudinal studies is needed to confirm this association. Future studies should investigate the role of type of diabetes and depression, diabetes distress and diabetes self-management behaviours. Our results may have clinical implications, as depressive symptoms and HbA1c levels could be targeted concurrently in the prevention and treatment of diabetes and depression

The effect of common infections on cognition and dementia in people with and without diabetes.

INTRODUCTION: Dementia is a major contributor to disability and dependence worldwide and is currently the leading cause of death in England. As the global burden of dementia continues to rise, identification of modifiable risk factors for dementia has become an urgent public health priority. Common infections may be associated with risk of dementia or cognitive impairment, but the nature, temporality or magnitude of any relationship is unclear. OBJECTIVES AND DATA SOURCES: The objectives of this thesis were to 1) systematically review evidence from longitudinal studies on the association between common clinically symptomatic bacterial infections and risk of incident dementia or cognitive decline, 2) examine the association of late-life infections with incident dementia using data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES), 3) investigate the association of midlife infections and incident dementia using data from the UK Biobank study, 4) investigate the association between midlife infections, cognitive decline and neuroimaging measures using data from the UK Biobank study. RESULTS: Evidence from 7 studies included in the systematic review (chapter 3) suggested that common clinically symptomatic bacterial infections were associated with an increased risk of dementia, with effect estimates ranging from HR 1.10 (95% CI; 1.02–1.19) to OR 2.60 (95% CI; 1.84–3.66) in a narrative synthesis of findings. However, studies were either from the United States or Taiwan, predominantly focused on hospitalised infections, mainly pneumonia or sepsis, and faced other methodological limitations including small sample sizes or inadequate confounder adjustment. Findings from my CPRD and HES study (chapter 5) showed that late life infections were associated with dementia risk in a population of 989,800 individuals aged 65 years and older. Dementia risk was higher for sepsis, pneumonia, infections resulting in hospital admission and among individuals with diabetes. In the third study (chapter 6) which compared the association of infections and dementia in a younger healthier population (the UK Biobank study), a lack of association was observed between the presence, site and setting of common midlife infections and dementia though consistent with the CPRD and HES study, an association was found for hospitalised infections. In the final study (chapter 7) which included 16,728 participants (median age 56.0 years [IQR 50.0-61.0]) midlife infections were not associated with cognitive decline on the mean correct response time, fluid intelligence and prospective memory tests. However, urinary tract infections and increasing numbers of infections were associated with slight declines in visual memory performance over time. No association was found between infections, hippocampal and white matter hyperintensity volume. CONCLUSION: Common late-life infections were associated with an increased risk of dementia, particularly for more severe infections (sepsis, pneumonia and infections resulting in hospital admission). However, mid-life infections were not associated with cognitive decline, hippocampal or white matter hyperintensity volume, with the exception of visual memory. Clinical trials are needed to investigate whether strategies to prevent infections lower subsequent dementia risk. In terms of cognitive decline, further studies with sufficient sample sizes for infection types and hospitalised infections, are needed to confirm the findings in this thesis

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories

The Impact of Different CD4 Cell-Count Monitoring and Switching Strategies on Mortality in HIV-Infected African Adults on Antiretroviral Therapy: An Application of Dynamic Marginal Structural Models

In Africa, antiretroviral therapy (ART) is delivered with limited laboratory monitoring, often none. In 2003-2004, investigators in the Development of Antiretroviral Therapy in Africa (DART) Trial randomized persons initiating ART in Uganda and Zimbabwe to either laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). CD4 cell counts were measured every 12 weeks in both groups but were only returned to treating clinicians for management in the LCM group. Follow-up continued through 2008. In observational analyses, dynamic marginal structural models on pooled randomized groups were used to estimate survival under different monitoring-frequency and clinical/immunological switching strategies. Assumptions included no direct effect of randomized group on mortality or confounders and no unmeasured confounders which influenced treatment switch and mortality or treatment switch and time-dependent covariates. After 48 weeks of first-line ART, 2,946 individuals contributed 11,351 person-years of follow-up, 625 switches, and 179 deaths. The estimated survival probability after a further 240 weeks for post-48-week switch at the first CD4 cell count less than 100 cells/mm(3) or non-Candida World Health Organization stage 4 event (with CD4 count <250) was 0.96 (95% confidence interval (CI): 0.94, 0.97) with 12-weekly CD4 testing, 0.96 (95% CI: 0.95, 0.97) with 24-weekly CD4 testing, 0.95 (95% CI: 0.93, 0.96) with a single CD4 test at 48 weeks (baseline), and 0.92 (95% CI: 0.91, 0.94) with no CD4 testing. Comparing randomized groups by 48-week CD4 count, the mortality risk associated with CDM versus LCM was greater in persons with CD4 counts of <100 (hazard ratio = 2.4, 95% CI: 1.3, 4.3) than in those with CD4 counts of ≥100 (hazard ratio = 1.1, 95% CI: 0.8, 1.7; interaction P = 0.04). These findings support a benefit from identifying patients immunologically failing first-line ART at 48 weeks