Methods applied to neonatal dried blood spot samples for secondary research purposes: a scoping review.

This scoping review aimed to synthesize the analytical techniques used and methodological limitations encountered when undertaking secondary research using residual neonatal dried blood spot (DBS) samples. Studies that used residual neonatal DBS samples for secondary research (i.e. research not related to newborn screening for inherited genetic and metabolic disorders) were identified from six electronic databases: Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Medline, PubMed and Scopus. Inclusion was restricted to studies published from 1973 and written in or translated into English that reported the storage, extraction and testing of neonatal DBS samples. Sixty-seven studies were eligible for inclusion. Included studies were predominantly methodological in nature and measured various analytes, including nucleic acids, proteins, metabolites, environmental pollutants, markers of prenatal substance use and medications. Neonatal DBS samples were stored over a range of temperatures (ambient temperature, cold storage or frozen) and durations (two weeks to 40.5 years), both of which impacted the recovery of some analytes, particularly amino acids, antibodies and environmental pollutants. The size of DBS sample used and potential contamination were also cited as methodological limitations. Residual neonatal DBS samples retained by newborn screening programs are a promising resource for secondary research purposes, with many studies reporting the successful measurement of analytes even from neonatal DBS samples stored for long periods of time in suboptimal temperatures and conditions.

Multiple Cardiac Biomarkers to Improve Prediction of Cardiovascular Events: Findings from the Generation Scotland Scottish Family Health Study.

BACKGROUND: Many studies have investigated whether single cardiac biomarkers improve cardiovascular risk prediction for primary prevention but whether a combined approach could further improve risk prediction is unclear. We aimed to test a sex-specific, combined cardiac biomarker approach for cardiovascular risk prediction. METHODS: In the Generation Scotland Scottish Family Health Study, N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor-15 (GDF-15), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and C-reactive protein (CRP) were measured in stored serum using automated immunoassays. Sex-specific Cox models that included SCORE2 risk factors evaluated addition of single and combined biomarkers for prediction of major adverse cardiovascular events (MACE). Combined biomarker models were compared to a baseline model that included SCORE2 risk factors. RESULTS: The study population comprised 18 383 individuals (58.9% women, median age of 48 years [25th-75th percentile, 35-58 years]). During the median follow up of 11.6 (25th-75th percentile, 10.8-13.0) years, MACE occurred in 942 (5.1%) individuals. The greatest increase in discrimination with addition of individual biomarkers to the base model was for women GDF-15 and for men NT-proBNP (change in c-index: + 0.010 for women and +0.005 for men). For women, combined biomarker models that included GDF-15 and NT-proBNP (+0.012) or GDF-15 and cTnI (+0.013), but not CRP or cTnT, further improved discrimination. For men, combined biomarker models that included NT-proBNP and GDF-15 (+0.007), NT-proBNP and cTnI (+0.006), or NT-proBNP and CRP (+0.008), but not cTnT, further improved discrimination. CONCLUSIONS: A combined biomarker approach, particularly the use of GDF-15, NT-proBNP and cTnI, further refined cardiovascular risk estimates.

Cardiovascular events and venous thromboembolism after primary malignant or non-malignant brain tumour diagnosis: a population matched cohort study in Wales (United Kingdom).

BACKGROUND: Elevated standardised mortality ratio of cardiovascular diseases (CVD) in patients with brain tumours may result from differences in the CVD incidences and cardiovascular risk factors. We compared the risk of CVD among patients with a primary malignant or non-malignant brain tumour to a matched general population cohort, accounting for other co-morbidities. METHODS: Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales (United Kingdom), we identified all adults aged ≥ 18 years in the primary care database with first diagnosis of malignant or non-malignant brain tumour identified in the cancer registry in 2000-2014 and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population without any cancer diagnosis. Outcomes included fatal and non-fatal major vascular events (stroke, ischaemic heart disease, aortic and peripheral vascular diseases) and venous thromboembolism (VTE). We used multivariable Cox models adjusted for clinical risk factors to compare risks, stratified by tumour behaviour (malignant or non-malignant) and follow-up period. RESULTS: There were 2869 and 3931 people diagnosed with malignant or non-malignant brain tumours, respectively, between 2000 and 2014 in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with a higher risk of VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12-28.88) and stroke (HR 3.32, 2.44-4.53). After the first year, the risks of VTE (HR 2.20, 1.52-3.18) and stroke (HR 1.45, 1.00-2.10) remained higher than controls. Patients with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73-5.06), stroke (HR 4.06, 3.35-4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26-3.48) within the first year of diagnosis compared with their controls. CONCLUSIONS: The elevated CVD and VTE risks suggested risk reduction may be a strategy to improve life quality and survival in people with a brain tumour.

Association of severe mental illness with stroke outcomes and process-of-care quality indicators: nationwide cohort study.

BACKGROUND: Severe mental illness (SMI) is associated with increased stroke risk, but little is known about how SMI relates to stroke prognosis and receipt of acute care. AIMS: To determine the association between SMI and stroke outcomes and receipt of process-of-care quality indicators (such as timely admission to stroke unit). METHOD: We conducted a cohort study using routinely collected linked data-sets, including adults with a first hospital admission for stroke in Scotland during 1991-2014, with process-of-care quality indicator data available from 2010. We identified pre-existing schizophrenia, bipolar disorder and major depression from hospital records. We used logistic regression to evaluate 30-day, 1-year and 5-year mortality and receipt of process-of-care quality indicators by pre-existing SMI, adjusting for sociodemographic and clinical factors. We used Cox regression to evaluate further stroke and vascular events (stroke and myocardial infarction). RESULTS: Among 228 699 patients who had had a stroke, 1186 (0.5%), 859 (0.4%), 7308 (3.2%) had schizophrenia, bipolar disorder and major depression, respectively. Overall, median follow-up was 2.6 years. Compared with adults without a record of mental illness, 30-day mortality was higher for schizophrenia (adjusted odds ratio (aOR) = 1.33, 95% CI 1.16-1.52), bipolar disorder (aOR = 1.37, 95% CI 1.18-1.60) and major depression (aOR = 1.11, 95% CI 1.05-1.18). Each disorder was also associated with marked increased risk of 1-year and 5-year mortality and further stroke and vascular events. There were no clear differences in receipt of process-of-care quality indicators. CONCLUSIONS: Pre-existing SMI was associated with higher risks of mortality and further vascular events. Urgent action is needed to better understand and address the reasons for these disparities.

Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities.

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, ß = -0.74, standard error (SE) = 0.13, P = 9.7 × 10-9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10-6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204-364; ß = 0.79, SE = 0.14, P = 9.4 × 10-8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (ß = 0.26, SE = 0.02, P = 2.9 × 10-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (ß = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10-4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54-35.25; P = 8.3 × 10-5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.

Conventional and Genetic Evidence on the Association between Adiposity and CKD.

BACKGROUND: The size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown. METHODS: Data from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR). RESULTS: Evidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06-genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively. CONCLUSIONS: Genetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD-associated risk.

Severe mental illness and mortality and coronary revascularisation following a myocardial infarction: a retrospective cohort study.

BACKGROUND: Severe mental illness (SMI), comprising schizophrenia, bipolar disorder and major depression, is associated with higher myocardial infarction (MI) mortality but lower coronary revascularisation rates. Previous studies have largely focused on schizophrenia, with limited information on bipolar disorder and major depression, long-term mortality or the effects of either sociodemographic factors or year of MI. We investigated the associations between SMI and MI prognosis and how these differed by age at MI, sex and year of MI. METHODS: We conducted a national retrospective cohort study, including adults with a hospitalised MI in Scotland between 1991 and 2014. We ascertained previous history of schizophrenia, bipolar disorder and major depression from psychiatric and general hospital admission records. We used logistic regression to obtain odds ratios adjusted for sociodemographic factors for 30-day, 1-year and 5-year mortality, comparing people with each SMI to a comparison group without a prior hospital record for any mental health condition. We used Cox regression to analyse coronary revascularisation within 30 days, risk of further MI and further vascular events (MI or stroke). We investigated associations for interaction with age at MI, sex and year of MI. RESULTS: Among 235,310 people with MI, 923 (0.4%) had schizophrenia, 642 (0.3%) had bipolar disorder and 6239 (2.7%) had major depression. SMI was associated with higher 30-day, 1-year and 5-year mortality and risk of further MI and stroke. Thirty-day mortality was higher for schizophrenia (OR 1.95, 95% CI 1.64-2.30), bipolar disorder (OR 1.53, 95% CI 1.26-1.86) and major depression (OR 1.31, 95% CI 1.23-1.40). Odds ratios for 1-year and 5-year mortality were larger for all three conditions. Revascularisation rates were lower in schizophrenia (HR 0.57, 95% CI 0.48-0.67), bipolar disorder (HR 0.69, 95% CI 0.56-0.85) and major depression (HR 0.78, 95% CI 0.73-0.83). Mortality and revascularisation disparities persisted from 1991 to 2014, with absolute mortality disparities more apparent for MIs that occurred around 70 years of age, the overall mean age of MI. Women with major depression had a greater reduction in revascularisation than men with major depression. CONCLUSIONS: There are sustained SMI disparities in MI intervention and prognosis. There is an urgent need to understand and tackle the reasons for these disparities.

Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank.

INTRODUCTION: Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. METHODS: Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. RESULTS: Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). DISCUSSION: These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk.

Genetically Determined Levels of Circulating Cytokines and Risk of Stroke.

BACKGROUND: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study. METHODS: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data. RESULTS: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls. CONCLUSIONS: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.

Common coding variant in SERPINA1 increases the risk for large artery stroke.

Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3'-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.

Genome-wide meta-analysis identifies 3 novel loci associated with stroke.

We conducted a European-only and transancestral genome-wide association meta-analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E-8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04-1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E-8, OR = 1.04, 95% CI = 1.03-1.06) and near DYRK1A (rs720470; p = 6.1E-9, OR = 1.05, 95% CI = 1.03-1.07) at genome-wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase-nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934-939.

Identifying dementia outcomes in UK Biobank: a validation study of primary care, hospital admissions and mortality data.

Prospective, population-based studies that recruit participants in mid-life are valuable resources for dementia research. Follow-up in these studies is often through linkage to routinely-collected healthcare datasets. We investigated the accuracy of these datasets for dementia case ascertainment in a validation study using data from UK Biobank-an open access, population-based study of > 500,000 adults aged 40-69 years at recruitment in 2006-2010. From 17,198 UK Biobank participants recruited in Edinburgh, we identified those with ≥ 1 dementia code in their linked primary care, hospital admissions or mortality data and compared their coded diagnoses to clinical expert adjudication of their full-text medical record. We calculated the positive predictive value (PPV, the proportion of cases identified that were true positives) for all-cause dementia, Alzheimer's disease and vascular dementia for each dataset alone and in combination, and explored algorithmic code combinations to improve PPV. Among 120 participants, PPVs for all-cause dementia were 86.8%, 87.3% and 80.0% for primary care, hospital admissions and mortality data respectively and 82.5% across all datasets. We identified three algorithms that balanced a high PPV with reasonable case ascertainment. For Alzheimer's disease, PPVs were 74.1% for primary care, 68.2% for hospital admissions, 50.0% for mortality data and 71.4% in combination. PPV for vascular dementia was 43.8% across all sources. UK routinely-collected healthcare data can be used to identify all-cause dementia in prospective studies. PPVs for Alzheimer's disease and vascular dementia are lower. Further research is required to explore the geographic generalisability of these findings.

Identifying dementia cases with routinely collected health data: A systematic review.

INTRODUCTION: Prospective, population-based studies can be rich resources for dementia research. Follow-up in many such studies is through linkage to routinely collected, coded health-care data sets. We evaluated the accuracy of these data sets for dementia case identification. METHODS: We systematically reviewed the literature for studies comparing dementia coding in routinely collected data sets to any expert-led reference standard. We recorded study characteristics and two accuracy measures-positive predictive value (PPV) and sensitivity. RESULTS: We identified 27 eligible studies with 25 estimating PPV and eight estimating sensitivity. Study settings and methods varied widely. For all-cause dementia, PPVs ranged from 33%-100%, but 16/27 were >75%. Sensitivities ranged from 21% to 86%. PPVs for Alzheimer's disease (range 57%-100%) were generally higher than those for vascular dementia (range 19%-91%). DISCUSSION: Linkage to routine health-care data can achieve a high PPV and reasonable sensitivity in certain settings. Given the heterogeneity in accuracy estimates, cohorts should ideally conduct their own setting-specific validation.

Comparisons of Risk Factors for Intracerebral Hemorrhage versus Ischemic Stroke in Chinese Patients.

BACKGROUND: Chinese populations have a higher stroke incidence, a higher proportion of intracerebral hemorrhage (ICH), and a lower proportion of ischemic stroke (IS) as compared with white populations. The reasons are not fully understood. METHODS: To evaluate the differences of major risk factors between ICH and IS in Chinese stroke patients, we analysed acute ICH and IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry from 2006 to 2011. We used multiple logistic regression models to examine the associations of risk factors with ICH vs. IS. Also, we conducted subgroup analyses when a strongly significant interaction was detected. RESULTS: We included a total of 1,373 ICH and 4,953 IS patients. ICH patients were younger than IS patients (mean age 61 vs. 68 years, p < 0.001), but there was no significant difference in gender (males 62 vs. 59%, p = 0.064). A logistic regression model adjusted for age, gender, and other major risk factors showed that both hypertension (OR 2.23, 95% CI 1.74-2.87) and alcohol intake (OR 1.44, 95% CI 1.16-1.77) had significantly stronger associations with ICH than IS, whereas diabetes, atrial fibrillation, ischemic heart disease, hyperlipidemia, smoking, and transient ischemic attack were less associated with ICH than IS. In subgroup analyses, the association of hypertension with ICH vs. IS was more marked in younger patients. CONCLUSION: Hypertension and alcohol intake are more strongly associated with ICH than IS in Chinese stroke patients, especially in younger patients.

Can mental health diagnoses in administrative data be used for research? A systematic review of the accuracy of routinely collected diagnoses.

BACKGROUND: There is increasing availability of data derived from diagnoses made routinely in mental health care, and interest in using these for research. Such data will be subject to both diagnostic (clinical) error and administrative error, and so it is necessary to evaluate its accuracy against a reference-standard. Our aim was to review studies where this had been done to guide the use of other available data. METHODS: We searched PubMed and EMBASE for studies comparing routinely collected mental health diagnosis data to a reference standard. We produced diagnostic category-specific positive predictive values (PPV) and Cohen's kappa for each study. RESULTS: We found 39 eligible studies. Studies were heterogeneous in design, with a wide range of outcomes. Administrative error was small compared to diagnostic error. PPV was related to base rate of the respective condition, with overall median of 76 %. Kappa results on average showed a moderate agreement between source data and reference standard for most diagnostic categories (median kappa = 0.45-0.55); anxiety disorders and schizoaffective disorder showed poorer agreement. There was no significant benefit in accuracy for diagnoses made in inpatients. CONCLUSIONS: The current evidence partly answered our questions. There was wide variation in the quality of source data, with a risk of publication bias. For some diagnoses, especially psychotic categories, administrative data were generally predictive of true diagnosis. For others, such as anxiety disorders, the data were less satisfactory. We discuss the implications of our findings, and the need for researchers to validate routine diagnostic data.

Formal and informal prediction of recurrent stroke and myocardial infarction after stroke: a systematic review and evaluation of clinical prediction models in a new cohort.

BACKGROUND: The objective of this study was to: (1) systematically review the reporting and methods used in the development of clinical prediction models for recurrent stroke or myocardial infarction (MI) after ischemic stroke; (2) to meta-analyze their external performance; and (3) to compare clinical prediction models to informal clinicians' prediction in the Edinburgh Stroke Study (ESS). METHODS: We searched Medline, EMBASE, reference lists and forward citations of relevant articles from 1980 to 19 April 2013. We included articles which developed multivariable clinical prediction models for the prediction of recurrent stroke and/or MI following ischemic stroke. We extracted information to assess aspects of model development as well as metrics of performance to determine predictive ability. Model quality was assessed against a pre-defined set of criteria. We used random-effects meta-analysis to pool performance metrics. RESULTS: We identified twelve model development studies and eleven evaluation studies. Investigators often did not report effective sample size, regression coefficients, handling of missing data; typically categorized continuous predictors; and used data dependent methods to build models. A meta-analysis of the area under the receiver operating characteristic curve (AUROCC) was possible for the Essen Stroke Risk Score (ESRS) and for the Stroke Prognosis Instrument II (SPI-II); the pooled AUROCCs were 0.60 (95% CI 0.59 to 0.62) and 0.62 (95% CI 0.60 to 0.64), respectively. An evaluation among minor stroke patients in the ESS demonstrated that clinicians discriminated poorly between those with and those without recurrent events and that this was similar to clinical prediction models. CONCLUSIONS: The available models for recurrent stroke discriminate poorly between patients with and without a recurrent stroke or MI after stroke. Models had a similar discrimination to informal clinicians' predictions. Formal prediction may be improved by addressing commonly encountered methodological problems.

Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke.

AIMS: Cerebral small vessel disease (SVD) causes a fifth of all strokes plus diffuse brain damage leading to cognitive decline, physical disabilities and dementia. The aetiology and pathogenesis of SVD are unknown, but largely attributed to hypertension or microatheroma. METHODS: We used the spontaneously hypertensive stroke-prone rat (SHRSP), the closest spontaneous experimental model of human SVD, and age-matched control rats kept under identical, non-salt-loaded conditions, to perform a blinded analysis of mRNA microarray, qRT-PCR and pathway analysis in two brain regions (frontal and mid-coronal) commonly affected by SVD in the SHRSP at age five, 16 and 21 weeks. RESULTS: We found gene expression abnormalities, with fold changes ranging from 2.5 to 59 for the 10 most differentially expressed genes, related to endothelial tight junctions (reduced), nitric oxide bioavailability (reduced), myelination (impaired), glial and microglial activity (increased), matrix proteins (impaired), vascular reactivity (impaired) and albumin (reduced), consistent with protein expression defects in the same rats. All were present at age 5 weeks thus predating blood pressure elevation. 'Neurological' and 'inflammatory' pathways were more affected than 'vascular' functional pathways. CONCLUSIONS: This set of defects, although individually modest, when acting in combination could explain the SHRSP's susceptibility to microvascular and brain injury, compared with control rats. Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human SVD.

APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis.

OBJECTIVES: Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the ε4 allele of the apolipoprotein E (APOE) gene is associated with the presence of CAA, both APOE-ε4 and ε2 are associated with lobar ICH. The generally accepted explanation is that APOE-ε4 promotes vascular amyloid deposition, while APOE-ε2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects. METHODS: We systematically identified published studies with data on APOE genotype and histopathological assessment of postmortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on progression to severe CAA. RESULTS: Of six eligible studies (543 eligible participants), data were available from 5 (497 participants, 353 with CAA). Meta-analyses showed a possible association of ε4+ genotypes with severe CAA (ε4+ vs ε4-: severe vs mild/moderate CAA, OR 2.5, 95% CI 1.4 to 4.5, p=0.002; severe vs moderate CAA, OR 1.7, 95% CI 0.9 to 3.1, p=0.11). For ε2+ versus ε2- genotypes, there was no significant association, but the very small number of participants with ε2+ genotypes (22) precluded reliable estimates. CONCLUSIONS: We found a possible association of severe CAA with APOE-ε4 but not APOE-ε2. However, our findings do not exclude a biologically meaningful association between APOE-ε2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.