Government of Western Australia Department of Health

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.

A debate has recently arisen over the use of racial classification in medicine and biomedical research. In particular, with the completion of a rough draft of the human genome, some have suggested that racial classification may not be useful for biomedical studies, since it reflects “a fairly small number of genes that describe appearance”1 and “there is no basis in the genetic code for race.”2 In part on the basis of these conclusions, some have argued for the exclusion of racial and ethnic classification from biomedical research.3 In the United States, race and ethnic background have been used as cause . . .

BACKGROUND: It is not known whether infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have a higher risk of birth defects than infants conceived naturally. METHODS: We obtained data from three registries in Western Australia on births, births after assisted conception, and major birth defects in infants born between 1993 and 1997. We assessed the prevalence of major birth defects diagnosed by one year of age in infants conceived naturally or with use of intracytoplasmic sperm injection or in vitro fertilization. RESULTS: Twenty-six of the 301 infants conceived with intracytoplasmic sperm injection (8.6 percent) and 75 of the 837 infants conceived with in vitro fertilization (9.0 percent) had a major birth defect diagnosed by one year of age, as compared with 168 of the 4000 naturally conceived infants (4.2 percent; P<0.001 for the comparison between either type of technology and natural conception). As compared with natural conception, the odds ratio for a major birth defect by one year of age, after adjustment for maternal age and parity, the sex of the infant, and correlation between siblings, was 2.0 (95 percent confidence interval, 1.3 to 3.2) with intracytoplasmic sperm injection, and 2.0 (95 percent confidence interval, 1.5 to 2.9) with in vitro fertilization. Infants conceived with use of assisted reproductive technology were more likely than naturally conceived infants to have multiple major defects and to have chromosomal and musculoskeletal defects. CONCLUSIONS: Infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have twice as high a risk of a major birth defect as naturally conceived infants.

BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimer's disease (AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants. METHODS: Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning. RESULTS: A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring. CONCLUSION: The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.

Classic parametric statistical significance tests, such as analysis of variance and least squares regression, are widely used by researchers in many disciplines, including psychology. For classic parametric tests to produce accurate results, the assumptions underlying them (e.g., normality and homoscedasticity) must be satisfied. These assumptions are rarely met when analyzing real data. The use of classic parametric methods with violated assumptions can result in the inaccurate computation of p values, effect sizes, and confidence intervals. This may lead to substantive errors in the interpretation of data. Many modern robust statistical methods alleviate the problems inherent in using parametric methods with violated assumptions, yet modern methods are rarely used by researchers. The authors examine why this is the case, arguing that most researchers are unaware of the serious limitations of classic methods and are unfamiliar with modern alternatives. A range of modern robust and rank-based significance tests suitable for analyzing a wide range of designs is introduced. Practical advice on conducting modern analyses using software such as SPSS, SAS, and R is provided. The authors conclude by discussing robust effect size indices.

BACKGROUND: The extent to which birth defects after infertility treatment may be explained by underlying parental factors is uncertain. METHODS: We linked a census of treatment with assisted reproductive technology in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of at least 400 g and registries of birth defects (including cerebral palsy and terminations for defects at any gestational period). We compared risks of birth defects (diagnosed before a child’s fifth birthday) among pregnancies in women who received treatment with assisted reproductive technology, spontaneous pregnancies (i.e., without assisted conception) in women who had a previous birth with assisted conception, pregnancies in women with a record of infertility but no treatment with assisted reproductive technology, and pregnancies in women with no record of infertility. RESULTS: Of the 308,974 births, 6163 resulted from assisted conception. The unadjusted odds ratio for any birth defect in pregnancies involving assisted conception (513 defects, 8.3%) as compared with pregnancies not involving assisted conception (17,546 defects, 5.8%) was 1.47 (95% confidence interval [CI], 1.33 to 1.62); the multivariate-adjusted odds ratio was 1.28 (95% CI, 1.16 to 1.41). The corresponding odds ratios with in vitro fertilization (IVF) (165 birth defects, 7.2%) were 1.26 (95% CI, 1.07 to 1.48) and 1.07(95% CI, 0.90 to 1.26), and the odds ratios with intracytoplasmic sperm injection (ICSI) (139 defects, 9.9%) were 1.77 (95% CI, 1.47 to 2.12) and 1.57 (95% CI, 1.30 to 1.90). A history of infertility, either with or without assisted conception, was also significantly associated with birth defects. CONCLUSIONS: The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded. (Funded by the National Health and Medical Research Council and the Australian Research Council.)

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

BACKGROUND: The North West Adelaide Health Study is a representative longitudinal cohort study of people originally aged 18 years and over. The aim of this study was to describe normative data for hand grip strength in a community-based Australian population. Secondary aims were to investigate the relationship between body mass index (BMI) and hand grip strength, and to compare Australian data with international hand grip strength norms. METHODS: The sample was randomly selected and recruited by telephone interview. Overall, 3 206 (81% of those recruited) participants returned to the clinic during the second stage (2004-2006) which specifically focused on the collection of information relating to musculoskeletal conditions. RESULTS: Following the exclusion of 435 participants who had hand pain and/or arthritis, 1366 men and 1312 women participants provided hand grip strength measurement. The study population was relatively young, with 41.5% under 40 years; and their mean BMI was 28.1 kg/m2 (SD 5.5). Higher hand grip strength was weakly related to higher BMI in adults under the age of 30 and over the age of 70, but inversely related to higher BMI between these ages. Australian norms from this sample had amongst the lowest of the hand grip strength of the internationally published norms, except those from underweight populations. CONCLUSIONS: This population demonstrated higher BMI and lower grip strength in younger participants than much of the international published, population data. A complete exploration of the relationship between BMI and hand grip strength was not fully explored as there were very few participants with BMI in the underweight range. The age and gender grip strength values are lower in younger adults than those reported in international literature.

BACKGROUND: The main objective of this methodological manuscript was to illustrate the role of using qualitative research in emergency settings. We outline rigorous criteria applied to a qualitative study assessing perceptions and experiences of staff working in Australian emergency departments. METHODS: We used an integrated mixed-methodology framework to identify different perspectives and experiences of emergency department staff during the implementation of a time target government policy. The qualitative study comprised interviews from 119 participants across 16 hospitals. The interviews were conducted in 2015-2016 and the data were managed using NVivo version 11. We conducted the analysis in three stages, namely: conceptual framework, comparison and contrast and hypothesis development. We concluded with the implementation of the four-dimension criteria (credibility, dependability, confirmability and transferability) to assess the robustness of the study, RESULTS: We adapted four-dimension criteria to assess the rigour of a large-scale qualitative research in the emergency department context. The criteria comprised strategies such as building the research team; preparing data collection guidelines; defining and obtaining adequate participation; reaching data saturation and ensuring high levels of consistency and inter-coder agreement. CONCLUSION: Based on the findings, the proposed framework satisfied the four-dimension criteria and generated potential qualitative research applications to emergency medicine research. We have added a methodological contribution to the ongoing debate about rigour in qualitative research which we hope will guide future studies in this topic in emergency care research. It also provided recommendations for conducting future mixed-methods studies. Future papers on this series will use the results from qualitative data and the empirical findings from longitudinal data linkage to further identify factors associated with ED performance; they will be reported separately.

OBJECTIVE: To measure the prevalence of obesity in Australian adults and to examine the associations of obesity with socioeconomic and lifestyle factors. DESIGN: AusDiab, a cross-sectional study conducted between May 1999 and December 2000, involved participants from 42 randomly selected districts throughout Australia. PARTICIPANTS: Of 20,347 eligible people aged > or = 25 years who completed a household interview, 11,247 attended the physical examination at local survey sites (response rate, 55%). MAIN OUTCOME MEASURES: Overweight and obesity defined by body mass index (BMI; kg/m(2)) and waist circumference (cm); sociodemographic factors (including smoking, physical activity and television viewing time). RESULTS: The prevalence of overweight and obesity (BMI > or = 25.0 kg/m(2); waist circumference > 80.0 cm [women] or > or = 94.0 cm [men]) in both sexes was almost 60%, defined by either BMI or waist circumference. The prevalence of obesity was 2.5 times higher than in 1980. Using waist circumference, the prevalence of obesity was higher in women than men (34.1% v 26.8%; P < 0.01). Lower educational status, higher television viewing time and lower physical activity time were each strongly associated with obesity, with television viewing time showing a stronger relationship than physical activity time. CONCLUSIONS: The prevalence of obesity in Australia has more than doubled in the past 20 years. Strong positive associations between obesity and each of television viewing time and lower physical activity time confirm the influence of sedentary lifestyles on obesity, and underline the potential benefits of reducing sedentary behaviour, as well as increasing physical activity, to curb the obesity epidemic.

OBJECTIVE: The goal of this study was to identify mental, behavioral, and cognitive disorders that may be triggered or exacerbated during heat waves, predisposing individuals to heat-related morbidity and mortality. DESIGN: Using health outcome data from Adelaide, South Australia, for 1993-2006, we estimated the effect of heat waves on hospital admissions and mortalities attributed to mental, behavioral, and cognitive disorders. We analyzed data using Poisson regression accounting for overdispersion and controlling for season and long-term trend, and we performed threshold analysis using hockey stick regression. RESULTS: Above a threshold of 26.7 degrees C, we observed a positive association between ambient temperature and hospital admissions for mental and behavioral disorders. Compared with non-heat-wave periods, hospital admissions increased by 7.3% during heat waves. Specific illnesses for which admissions increased included organic illnesses, including symptomatic mental disorders; dementia; mood (affective) disorders; neurotic, stress related, and somatoform disorders; disorders of psychological development; and senility. Mortalities attributed to mental and behavioral disorders increased during heat waves in the 65- to 74-year age group and in persons with schizophrenia, schizotypal, and delusional disorders. Dementia deaths increased in those up to 65 years of age. CONCLUSION: Our results suggest that episodes of extreme heat pose a salient risk to the health and well-being of the mentally ill. RELEVANCE TO CLINICAL OR PROFESSIONAL PRACTICE: Improvements in the management and care of the mentally ill need to be addressed to avoid an increase in psychiatric morbidity and mortality as heat waves become more frequent.

Objective The clinical significance of 2 main dimensions of perfectionism (perfectionistic strivings and perfectionistic concerns) was examined via a meta‐analysis of studies investigating perfectionism in the psychopathology literature. Method We investigated relationships between psychopathology outcomes (clinical diagnoses of depression, anxiety disorders, obsessive‐compulsive disorder, and eating disorders; symptoms of these disorders; and outcomes related to psychopathology, such as deliberate self‐harm, suicidal ideation, and general distress) and each perfectionism dimension. The relationships were examined by evaluating (a) differences in the magnitude of association of the 2 perfectionism dimensions with psychopathology outcomes and (b) subscales of 2 common measures of perfectionism. Results A systematic literature search retrieved 284 relevant studies, resulting in 2,047 effect sizes that were analysed with meta‐analysis and meta‐regression while accounting for data dependencies. Conclusion Findings support the notion of perfectionism as a transdiagnostic factor by demonstrating that both dimensions are associated with various forms of psychopathology.

Background: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD. Methods: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions. Results: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250–1:397; similar between children [1:364] and adults [1:303], P =0.60; across World Health Organization regions where data were available, P =0.29; and between population-based and electronic health records–based studies, P =0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200–289) compared with larger cohorts (1:365–407; P &lt;0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12–1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12–1:23]). Between-study heterogeneity was large ( I 2 &gt;95%). Tests assessing bias were nonsignificant ( P &gt;0.3). Conclusions: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

BACKGROUND: Eight randomized trials have evaluated whether the prophylactic use of an implantable cardioverter-defibrillator (ICD) improves survival among patients who are at risk for sudden death due to left ventricular systolic dysfunction but who have not had a life-threatening ventricular arrhythmia. We assessed the cost-effectiveness of the ICD in the populations represented in these primary-prevention trials. METHODS: We developed a Markov model of the cost, quality of life, survival, and incremental cost-effectiveness of the prophylactic implantation of an ICD, as compared with control therapy, among patients with survival and mortality rates similar to those in each of the clinical trials. We modeled the efficacy of the ICD as a reduction in the relative risk of death on the basis of the hazard ratios reported in the individual clinical trials. RESULTS: Use of the ICD increased lifetime costs in every trial. Two trials--the Coronary Artery Bypass Graft (CABG) Patch Trial and the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT)--found that the prophylactic implantation of an ICD did not reduce the risk of death and thus was both more expensive and less effective than control therapy. For the other six trials--the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I, MADIT II, the Multicenter Unsustained Tachycardia Trial (MUSTT), the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)--the use of an ICD was projected to add between 1.01 and 2.99 quality-adjusted life-years (QALY) and between 68,300 dollars and 101,500 dollars in cost. Using base-case assumptions, we found that the cost-effectiveness of the ICD as compared with control therapy in these six populations ranged from 34,000 dollars to 70,200 dollars per QALY gained. Sensitivity analyses showed that this cost-effectiveness ratio would remain below 100,000 dollars per QALY as long as the ICD reduced mortality for seven or more years. CONCLUSIONS: Prophylactic implantation of an ICD has a cost-effectiveness ratio below 100,000 dollars per QALY gained in populations in which a significant device-related reduction in mortality has been demonstrated.

This review examines the current evidence for a possible connection between nutritional intake (including micronutrients and whole diet) and neurocognitive development in childhood. Earlier studies which have investigated the association between nutrition and cognitive development have focused on individual micronutrients, including omega-3 fatty acids, vitamin B12, folic acid, choline, iron, iodine, and zinc, and single aspects of diet. The research evidence from observational studies suggests that micronutrients may play an important role in the cognitive development of children. However, the results of intervention trials utilizing single micronutrients are inconclusive. More generally, there is evidence that malnutrition can impair cognitive development, whilst breastfeeding appears to be beneficial for cognition. Eating breakfast is also beneficial for cognition. In contrast, there is currently inconclusive evidence regarding the association between obesity and cognition. Since individuals consume combinations of foods, more recently researchers have become interested in the cognitive impact of diet as a composite measure. Only a few studies to date have investigated the associations between dietary patterns and cognitive development. In future research, more well designed intervention trials are needed, with special consideration given to the interactive effects of nutrients.

BACKGROUND: There have been few large epidemiological studies examining the association between thyroid dysfunction and cardiovascular disease. In particular, it is uncertain if subclinical hypothyroidism is a risk factor for cardiovascular disease. METHODS: Serum thyrotropin and free thyroxine concentrations were measured in 2108 archived serum samples from a 1981 community health survey in Busselton, Western Australia (Busselton Health Study). In a cross-sectional study, we examined the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction. In a longitudinal study, we examined the risk of cardiovascular mortality and coronary heart disease events (fatal and nonfatal combined) to the end of 2001 (excluding subjects who had coronary heart disease at baseline). RESULTS: In the cross-sectional analysis, subjects with subclinical hypothyroidism (n = 119) had a significantly higher prevalence of coronary heart disease than euthyroid subjects (n = 1906) (age- and sex-adjusted prevalence odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). In the longitudinal analysis of subjects with subclinical hypothyroidism (n = 101), there were 21 cardiovascular deaths observed compared with 9.5 expected (age- and sex-adjusted hazard ratio, 1.5; 95% confidence interval, 1.0-2.4; P = .08) and 33 coronary heart disease events observed compared with 14.7 expected (age- and sex-adjusted hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P < .01). The increased risk of coronary heart disease events remained significant after further adjustment for standard cardiovascular risk factors. Subjects with subclinical hyperthyroidism (n = 39) had no adverse outcomes. CONCLUSION: Subclinical hypothyroidism may be an independent risk factor for coronary heart disease.