Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (Cindex) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction

Asymptotic and small sample statistical properties of random frailty variance estimates for shared gamma frailty models

This paper concerns maximum likelihood estimation for the semiparametric shared gamma frailty model; that is the Cox proportional hazards model with the hazard function multiplied by a gamma random variable with mean 1 and variance θ. A hybrid ML-EM algorithm is applied to 26400 simulated samples of 400 to 8000 observations with Weibull hazards. The hybrid algorithm is much faster than the standard EM algorithm, faster than standard direct maximum likelihood (ML, Newton Raphson) for large samples, and gives almost identical results to the penalised likelihood method in S-PLUS 2000. When the true value θ0 of θ is zero, the estimates of θ are asymptotically distributed as a 50-50 mixture between a point mass at zero and a normal random variable on the positive axis. When θ0 > 0> the asymptotic distribution is normal. However, for small samples, simulations suggest that the estimates of θ are approximately distributed as an x -(100 -x)% mixture, 0≤ x ≤50, between a point mass at zero and a normal random variable on the positive axis even for θ0 > 0. In light of this, p-values and confidence intervals need to be adjusted accordingly. We indicate an approximate method for carrying out the adjustment

Combining multiple comorbidities with Acute Physiology Score to predict hospital mortality of critically ill patients: a linked data cohort study

We investigated whether replacing the Acute Physiology and Chronic Health Evaluation (APACHE) II weighted comorbidity score with other measures of prior comorbidity would improve the prediction of hospital mortality in critically ill patients. Clinical data of 24 303 critically ill patients were linked to the Western Australian hospital morbidity database to identify prior comorbidities. Minor comorbidities as described in the Charlson comorbidity index and Elixhauser comorbidities were prevalent in critically ill patients. Among 24 303 admissions, 3615 (14.9%), 10 223 (42.1%), and 11 597 (47.7%) patients had at least one comorbidity as defined in the APACHE II score, Charlson comorbidity index, and Elixhauser comorbidities, respectively. The ability of comorbidity alone to discriminate between hospital survivors and non-survivors was poor. Replacing the APACHE II weighted comorbidity score with other more comprehensive measures of comorbidity did not significantly improve the discrimination of the APACHE II score

Body mass index is a stronger predictor of alanine aminotransaminase levels than alcohol consumption

Background and Aims:  The relative effects of obesity compared to alcohol on liver injury are uncertain. We examined their effects on alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) levels in a population-based cohort. Methods:  Adult residents (2610: 1326 males, 1284 females) from Busselton, Australia, participated in a cross-sectional survey determining alcohol intake as determined by a validated questionnaire, anthropometric measurements and serum analysis. Alcohol consumption was classified as never, light (420 g/week). Results:  The majority of subjects were either overweight (41%) or obese (17%). A minority of subjects were moderate (25%) or heavy drinkers (4%). Body mass index (BMI) and waist circumference were strongly associated with ALT and GGT (P 0.2 for all tests). Conclusions:  Excess weight is more common than excessive alcohol consumption in the community and confers a greater risk of elevated aminotransaminase levels

Serum ferritin and cardiovascular disease: A 17-Year Follow-up study in Busselton, Western Australia

The association between serum ferritin level and coronary heart disease (CHD) and stroke events was evaluated in a long-term Western Australia prospective study in 1981–1998. The cohort consisted of the 1,612 men and women aged 40–89 years who participated in the 1981 Busselton Health Survey and who were free of cardiovascular disease at that time. Serum ferritin levels were obtained from serum samples stored frozen since 1981. The outcomes of interest were time to first CHD event (hospital admission or death) and time to first stroke event. Case-cohort sampling was used to reduce costs and preserve serum but still allow efficient analysis. Ferritin assays were performed for 217 CHD cases, 118 stroke cases, and a random sample of 450 of the total cohort. Proportional hazards regression models were used to obtain age-adjusted and multivariate-adjusted hazard ratios for ferritin level in relation to CHD and stroke. The hazard ratio for the highest tertile group compared with the lowest group was 0.96 (95% confidence interval: 0.60, 1.53) for CHD and 1.43 (95% confidence interval: 0.78, 2.64) for stroke. Little or no evidence was found that ferritin level was a risk factor for cardiovascular disease

NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: An Eleven-Year follow-up study

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) uncommonly results in cirrhosis and liver-related death; however, its impact on the development of metabolic complications remains unclear. We sought to determine whether NAFLD with elevated aminotransaminase (ALT) levels was a risk factor for incident diabetes or the metabolic syndrome (MS) over an 11-year period. METHODS: Adult residents of Busselton, Western Australia underwent assessment in 1994-1995 as part of the Busselton Health Survey. NAFLD was diagnosed on the basis of a raised ALT (>40 IU/l) after the exclusion of alcohol, viral, metabolic, and autoimmune liver disease. NAFLD and non-NAFLD subjects were reassessed in 2005 for liver complications, diabetes, and the MS. RESULTS: A total of 358 subjects, 68% male (109 NAFLD, 249 non-NAFLD), mean age (s.d.) 59.9 (11.6) years, attended follow-up 11.1 years after the initial assessment. After excluding subjects with diabetes at baseline, those with NAFLD were more likely to have developed diabetes on follow-up (20/106, 18.9% vs. 15/246, 6.1%; P<0.001). After excluding subjects with MS at baseline, those with NAFLD were more likely to have developed MS at follow-up (27/81, 33.3% vs. 51/226, 22.6%; P=0.056). However, in multivariate logistic regression models, NAFLD was no longer a significant independent predictor of the development of diabetes or MS after adjusting for baseline waist circumference, hypertension, and insulin resistance. None of the subjects developed liver complications. CONCLUSIONS: Subjects with NAFLD and elevated ALT levels are at an increased risk of developing diabetes and the MS. This may be because of the presence of associated metabolic risk factors

A Cross-Sectional community study of serum iron measures and cognitive status in older adults

The relationship of iron status with cognition and dementia risk in older people is contentious. We have examined the longitudinal relationship between serum ferritin and cognition in 800 community-dwelling Australians 60 years or older. Iron studies (serum iron, transferrin saturation, serum ferritin) were performed in 1994/5 and 2003/4 and clinical and cognitive assessments were conducted in 2003/4 for 800 participants of the Busselton Health Study. All participants completed the Cambridge Cognitive test (CAMCOG). Those with CAMCOG scores 0.05). In participants without dementia (n=749), neither serum ferritin in 1994/5 or 2003/4 nor change in serum ferritin between these times was related to total CAMCOG or executive function scores, with or without adjustment for gender, age, National Adult reading test, or stroke history (all p> 0.05). No relationships were observed between ferritin and cognition for participants with possible or probable dementia (n=51). All participants identified as HFE C282Y homozygous or with serum ferritin >1,000 ng/ml had normal CAMCOG scores. We conclude abnormal body iron stores (low or high) are unlikely to have clinically significant effects on cognition or dementia risk in community-dwelling older people

Population-based study of the relationship between mutations in the hemochromatosis (HFE) gene and arthritis

Background and Aim:  Mutations in the hemochromatosis (HFE) gene are carried by one in three individuals of British Isles descent and may result in increased iron stores. These increased iron stores could potentially induce or exacerbate diseases, such as arthritis, in which iron has a role in pathogenesis. Although arthritis is a well-known association of clinically overt hereditary hemochromatosis, controversy surrounds the role of mutations in the HFE gene as risk factors for arthritis. The aim of the present study was to determine whether mutations in the HFE gene are associated with an increased prevalence of arthritis. Methods:  A population-based study was conducted in Busselton, Western Australia, of the prevalence of arthritis in 1372 individuals of British Isles descent. Participants completed a questionnaire and general physical examination. Analysis for C282Y and H63D HFE mutations was undertaken. Unadjusted and adjusted odds ratios (OR) were calculated for the relationship between HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis. Results:  There was no association between the presence of HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis (C282Y/wild type (WT) adjusted OR = 1.041 (95% confidence interval (CI) 0.68–1.61), H63D/WT OR = 0.76 (95% CI 0.53–1.08), C282Y/C282Y OR = 0.39 (95% CI 0.04–3.63), C282Y/H 63D OR = 0.808 (95% CI 0.27–2.42), H63D/H63D OR = 0.419 (95% CI 0.13–1.36)). Overall adjusted OR for arthritis in participants with one or more HFE mutations was 0.81 (95% CI 0.61–1.09). Conclusions:  Mutations of the HFE gene are not risk factors for arthritis in populations of British Isles descent

Comparison of Acute Physiology and Chronic Health Evaluation (APACHE) II score with organ failure scores to predict hospital mortality

This study compared the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) II score with two organ failure scores in predicting hospital mortality of critically ill patients. A total of 1311 consecutive adult patients in a tertiary 22-bed multidisciplinary intensive care unit (ICU) in Western Australia were considered. The APACHE II score had a better calibration and discrimination than the Max Sequential Organ Failure Score (Max SOFA) (area under receiver operating characteristic (ROC) curve 0.858 vs 0.829), Admission SOFA (area under ROC 0.858 vs 0.791), and the first day or cumulative 5-day Royal Perth Hospital Intensive Care Unit (RPHICU) organ failure score (area under ROC 0.858 vs 0.822 and 0.819, respectively) in predicting hospital mortality. The APACHE II score predicted hospital mortality of critically ill patients better than the SOFA and RPHICU organ failure scores in our ICU

A prospective study of infection and cardiovascular diseases: the Busselton Health Study

Background: Infectious agents might play a role in the aetiology of cardiovascular diseases. The aim was to determine the association of antibodies to implicated infectious agents with coronary heart disease (CHD) and stroke in a population-based prospective study. Design: This study was based on a cohort of 1612 cardiovascular disease-free adults in the 1981 Busselton Health Survey. Primary risk factors were measured from stored serum and case-cohort sampling was used to reduce costs and preserve serum. The outcomes of interest were time to first CHD or stroke event Serum antibody tests were carried out for all 218 CHD cases, all 119 stroke cases and a random subset of 451 subjects. Methods: Sera were tested for antibodies to Chlamydia pneumoniae (IgG and IgA), and for IgG antibodies to Helicobacter pylori and cytomegalovirus (CMV). The association between serum antibody and risk of cardiovascular diseases was analysed using Cox proportional hazards regression. Results: The estimated population prevalence was 24% for C. pneumoniae IgG, 7% for C. pneumoniae IgA, 58% for H. pylori and 85% had CMV antibody levels greater than 15 AU/mL. The estimated relative risk of CHD was around 1.2 for all antibodies examined, except for C. pneumoniae IgA for which it was less than one, and the estimated relative risk of stroke was around 0.85, however in all cases the 95% confidence interval included one. Conclusions: This study of an Australian population does not support an association between serum antibody levels to C. pneumoniae, H. pylori and CMV with development of cardiovascular diseases