Data linkage in an established longitudinal cohort: the Western Australian Pregnancy Cohort (Raine) Study.

The Western Australian Data Linkage System is one of a few comprehensive, population-based data linkage systems worldwide, creating links between information from different sources relating to the same individual, family, place or event, while maintaining privacy. The Raine Study is an established cohort study with more than 2000 currently active participants. Individual consent was obtained from participants for information in publicly held databases to be linked to their study data. A waiver of consent was granted where it was impracticable to obtain consent. Approvals to link the datasets were obtained from relevant ethics committees and data custodians. The Raine Study dataset was subsequently linked to academic testing data collected by the Western Australian Department of Education. Examination of diet and academic performance showed that children who were predominantly breastfed for at least 6 months scored higher academically at age 10 than children who were breastfed for less than 6 months. A further study found that better diet quality at ages 1, 2 and 3 years was associated with higher academic scores at ages 10 and 12 years. Examination of nutritional intake at 14 years of age found that a better dietary pattern was associated with higher academic performance. The detailed longitudinal data collected in the Raine Study allowed for adjustment for multiple covariates and confounders. Data linkage reduces the burden on cohort participants by providing additional information without the need to contact participants. It can give information on participants who have been lost to follow-up; provide or complement missing data; give the opportunity for validation studies comparing recall of participants with administrative records; increase the population sample of studies by adding control participants from the general population; and allow for the adjustment of multiple covariates and confounders. The Raine Study dataset is extensive and detailed, and can be further improved by linking to other external data sources. By linking educational outcomes to the Raine Study database, it was shown across three different age groups that a healthy diet was consistently associated with higher academic performance.

Genetic and environmental factors in conjunctival UV autofluorescence.

IMPORTANCE: Conjunctival UV autofluorescence (CUVAF) photography was developed to detect and characterize preclinical sunlight-induced ocular damage. Ocular sun exposure has been related to cases of pterygia and was recently negatively correlated with myopia. Hence, CUVAF has excellent potential as an objective biomarker of sun exposure. However, much variation in CUVAF has been observed, and the relative contributions of genes and environment to this variation have not yet been identified. OBJECTIVE: To investigate sources of variation in CUVAF in relation to its potential clinical relevance. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional analysis of 3 population-based cohort studies in the general community, including the Twins Eye Study in Tasmania, the Brisbane Adolescent Twin Study, and the Western Australian Pregnancy Cohort (Raine) Study. The twin studies were conducted between 2001 and 2009, and the 20-year follow-up of the Raine Study was completed between March 2010 and February 2012. We included genotypic and phenotypic data from 295 Australian families in the Tasmanian and Brisbane twin studies and from 661 participants in the 20-year follow-up of the Raine Study. We compared CUVAF levels in the 3 cohorts and performed a classic twin study to partition variation in CUVAF. We also conducted a genome-wide association analysis to identify specific genetic variants associated with CUVAF. MAIN OUTCOMES AND MEASURES: The total area of CUVAF, heritability of CUVAF, and single-nucleotide polymorphisms (SNPs) associated with CUVAF from the genome-wide association study. RESULTS: Within twin cohorts, individuals living closer to the equator (latitude, 27.47° S) had higher levels of CUVAF compared with individuals from southern regions (latitude, 42.88° S) (median [interquartile range], 45.4 [26.8-68.5] vs 28.7 [15.0-42.3] mm2; P < .001). The variation in CUVAF explained by the additive genetic component was 0.37 (95% CI, 0.22-0.56), whereas the variation due to the common environment was 0.50 (95% CI; 0.29-0.71). The SNP rs1060043, located approximately 800 base pairs away from the SLC1A5 gene, a member of the solute carrier family 1, had a genome-wide significant association with a P value of 3.2 × 10-8. Gene-based analysis did not improve our power to detect association with other genes. CONCLUSIONS AND RELEVANCE: Our findings confirm that, although a large environmental component to CUVAF (equivalent of sun exposure) exists, genes also play a significant role. We identified a SNP (rs1060043) as being significantly associated with CUVAF; replication of this finding in future studies is warranted.

Vitamin D in fetal development: findings from a birth cohort study.

Birth cohort studies provide an invaluable resource for studies of the influence of the fetal environment on health in later life. It is uncertain to what extent maternal vitamin D status influences fetal development. Using an unselected community-based cohort of 901 mother-offspring pairs (the Western Australian Pregnancy Cohort [Raine] Study), we examined the relationship between maternal vitamin D deficiency at 18 weeks' pregnancy and long-term health outcomes of offspring who were born in Perth, Western Australia (32° South), in 1989-1991. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) was present in 36% (323 of 901) of the pregnant women. After adjusting for relevant covariates, maternal vitamin D deficiency during pregnancy was associated with impaired lung development in 6-year-old offspring, neurocognitive difficulties at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at 20 years. In summary, vitamin D may have an important, multifaceted role in the development of fetal lungs, brain, and bone. Experimental animal studies support an active contribution of vitamin D to organ development. Randomized controlled trials of vitamin D supplementation in pregnant women with long-term follow-up of offspring are urgently required to examine whether the correction of vitamin D deficiency in pregnant women is beneficial for their offspring and to determine the optimal level of maternal serum 25(OH)D for fetal development.

Myopia is associated with lower vitamin D status in young adults.

PURPOSE: To investigate the association between serum vitamin D levels and myopia in young adults. METHODS: A total of 946 individuals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia, and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including postcycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations were determined using mass spectrometry. The association between serum 25(OH)D3 concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ -0.5 diopters. RESULTS: Of the 946 participants, 221 (23.4%) had myopia (n = 725 nonmyopic). Myopic subjects had lower serum 25(OH)D3 concentrations compared to nonmyopic participants (median 67.6 vs. 72.5 nmol, P = 0.003). In univariable analysis, lower serum 25(OH)D3 concentration was associated with higher risk of having myopia (odds ratio [OR] for <50 vs. ≥50 nmol/L: 2.63; confidence interval [95% CI] 1.71-4.05; P < 0.001). This association persisted after adjustment for potential confounders, including age, sex, ethnicity, parental myopia, education status, and ocular sun-exposure biomarker score (adjusted OR 2.07; 95% CI 1.29-3.32; P = 0.002). CONCLUSIONS: Myopic participants had significantly lower 25(OH)D3 concentrations. The prevalence of myopia was significantly higher in individuals with vitamin D deficiency compared to the individuals with sufficient levels. Longitudinal studies are warranted to investigate whether higher serum 25(OH)D3 concentration is protective against myopia or whether it is acting as a proxy for some other biologically effective consequence of sun exposure.

Comparison of monochromatic aberrations in young adults with different visual acuity and refractive errors.

PURPOSE: To compare the monochromatic aberrations in a large cohort of 20-year-old Australians with differing levels of visual acuity and explore the relationship between these aberrations and refractive error. SETTING: Lions Eye Institute, Perth, Western Australia, Australia. DESIGN: Cross-sectional analysis of a population-based cohort. METHODS: Monochromatic aberrations were measured using a Zywave II wavefront aberrometer with natural pupils in a dark room. The logMAR corrected distance visual acuity (CDVA) was measured monocularly under normal illumination. Cycloplegic autorefraction was also performed. RESULTS: The study enrolled 2039 eyes of 1040 participants. Data from 1007 right eyes were analyzed. The median CDVA and spherical equivalent were -0.06 logMAR (interquartile range [IQR], -0.10 to 0.00) and +0.25 diopters (D) (IQR, -0.38 to 0.63), respectively. The median 6.0 mm higher-order aberration (HOA) was 0.58 µm (IQR, 0.44 to 0.79). Coma-like aberrations and 3rd-, 4th-, and 5th-order HOAs were significantly different between subjects with a CDVA of -0.10 logMAR or better and those with a CDVA worse than -0.10 logMAR. Fourth-order aberrations Z(4,-4) (P=.024) and Z(4,-2) (P=.029) and 2nd-order aberration Z(2,0) (P<.001) differed significantly between myopic eyes, emmetropic eyes, and hyperopic eyes. Subjects with higher myopia had slightly higher total HOAs. CONCLUSIONS: The HOAs in this population were marginally higher than previously reported values. The findings confirm there is a difference in monochromatic aberrations between different vision and refractive groups. Results in this study will benefit decision-making processes in the clinical setting.

Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry: results of a genome-wide association study.

PURPOSE: Corneal astigmatism is a common eye disorder characterized by irregularities in corneal curvature. Recently, the rs7677751 single nucleotide polymorphism (SNP) at the platelet-derived growth factor receptor alpha (PDGFRA) locus was found to be associated with corneal astigmatism in people of Asian ancestry. In the present study, we sought to replicate this finding and identify other genetic markers of corneal astigmatism in an Australian population of Northern European ancestry. METHODS: Data from two cohorts were included in this study. The first cohort consisted of 1,013 individuals who were part of the Western Australian Pregnancy Cohort (Raine) Study: 20-year follow-up Eye Study. The second cohort comprised 1,788 individuals of 857 twin families who were recruited through the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study. Corneal astigmatism was calculated as the absolute difference between the keratometry readings in two meridians, and genotype data were extracted from genome-wide arrays. Initially, each cohort was analyzed separately, before being combined for meta- and subsequent genome-wide pathway analysis. RESULTS: Following meta-analysis, SNP rs7677751 at the PDGFRA locus had a combined p=0.32. No variant was found to be statistically significantly associated with corneal astigmatism at the genome-wide level (p<5.0×10(-8)). The SNP with strongest association was rs1164064 (p=1.86×10(-6)) on chromosome 3q13. Gene-based pathway analysis identified a significant association between the Gene Ontology "segmentation" (GO:0035282) pathway, corrected p=0.009. CONCLUSIONS: Our data suggest that the PDGFRA locus does not transfer a major risk of corneal astigmatism in people of Northern European ancestry. Better-powered studies are required to validate the novel putative findings of our study.

A geometric morphometric assessment of hand shape and comparison to the 2D:4D digit ratio as a marker of sexual dimorphism.

Twin studies are extremely useful for investigating hypotheses of genetic influence on a range of behavioral and physical traits in humans. Studies of physical traits, however, are usually limited to size-related biological characteristics because it is inherently difficult to quantify the morphological counterpart - shape. In recent years, the development of geometry-preserving analytical techniques built upon multivariate statistical methodologies has produced a new discipline in biological shape analysis known as geometric morphometrics. In this study of hand shape analysis, we introduce the reader already familiar with the field of twin research to the potential utility of geometric morphometrics and demonstrate the cross-discipline applicability of methods. We also investigate and compare the efficacy of the 2D:4D ratio, a commonly used marker of sexual dimorphism, to the fully multivariate approach of shape analysis in discriminating between male and female sex. Studies of biological shape variation utilizing geometric morphometric techniques may be completed with software freely available on the Internet and time invested to master the small learning curve in concepts and theory.

Raine eye health study: design, methodology and baseline prevalence of ophthalmic disease in a birth-cohort study of young adults.

PURPOSE: The Raine Eye Health Study (REHS) was conceived to determine the prevalence of and risk factors for eye disease in young adults, and to characterize ocular biometric parameters in a young adult cohort. This article summarizes the rationale and study design of REHS and outlines the baseline prevalence of ophthalmic disease in this population. METHODS: The Western Australian Pregnancy Cohort (Raine) Study originated as a randomized-controlled trial of 2900 women recruited from the state's largest maternity hospital. Their offspring (N = 2868) have been followed at birth, ages 1, 2, 3, 5, 8, 10, 14, 17 and 20 years of age in a prospective cohort study. DNA has been collected from participants for genome-wide association studies. At the 20-year follow-up participants completed a comprehensive eye assessment that included visual acuity, orthoptic assessment and cycloplegic autorefraction, as well as several ocular biometric variables and multiple ophthalmic photographs of the anterior and posterior segments. RESULTS: A total of 1344 participants (51.3% male) were assessed over a 24-month period. For the majority of examined participants (85.5%) both parents were Caucasian, 63.3% had completed school year 12 or equivalent, 5.5% had myopia (spherical equivalent ≤-3 diopters) and 15 participants (1.2%) had unilateral or bilateral pterygia. Keratoconus, cataract, keratitis and uveitis were rare. CONCLUSION: The REHS design and methodology allow comparison with other population-based studies of eye disease. The study established the prevalence of eye disorders in a large sample of predominantly Caucasian young Australian adults.

Genetic variants near PDGFRA are associated with corneal curvature in Australians.

PURPOSE: Irregularity in the corneal curvature (CC) is highly associated with various eye disorders such as keratoconus and myopia. The sample had limited power to find genomewide significant (5 × 10(-8)) hits but good power for replication. Thus, an attempt was made to test whether alleles in the FRAP1 and PDGFRA genes, recently found to be associated with CC in Asian populations, also influence CC in Australians of North European ancestry. Results of initial genomewide association studies (GWAS) for CC in Australians were also reported. METHODS: Two population-based cohorts of 1788 Australian twins and their families, as well as 1013 individuals from a birth cohort from Western Australia, were genotyped using genomewide arrays. Following separate individual analysis and quality control, the results from each cohort underwent meta-analysis. RESULTS: Meta-analysis revealed significant replication of association between rs2114039 and corneal curvature (P = 0.0045). The SNP rs2114039 near PDGFRA has been previously implicated in Asians. No SNP at the FRAP1 locus was found to be associated in our Australian samples. No SNP surpassed the genomewide significance threshold of 5 × 10(-8). The SNP with strongest association was rs2444240 (P = 3.658 × 10(-7)), which is 31 kb upstream to the TRIM29 gene. CONCLUSIONS: A significant role of the PDGFRA gene in determining corneal curvature in the Australian population was confirmed in this study, also highlighting the putative association of the TRIM29 locus with CC.

Role of the TCF4 gene intronic variant in normal variation of corneal endothelium.

PURPOSE: To identify early features of Fuchs endothelial dystrophy (FED) in carriers of the rs613872(G) transcription factor 4 gene (TCF4) aged 20 to 21 years. METHODS: Prospective cohort study of people aged 20 to 21 years previously enrolled in the Western Australia Pregnancy (Raine) Cohort. Specular microscopy was performed using a noncontact specular microscopy (EM-3000; Tomey, Nagoya, Japan). Individual genotype data were extracted from the genome-wide Illumina 660 Quad Array. Analysis of the association between the rs613872 risk allele in TCF4 and specular microscopic measurements was conducted. RESULTS: Association between the rs613872 risk allele and corneal endothelial cell density (CD) as well as the coefficient of variation in cell shape was the main outcome measure. Genotype and specular microscopic data were available for a total of 445 participants (46% women). The median CD was 2851 and 2850 cells per square millimeter in the right and left eyes, respectively. No significant differences between intereye variability in endothelial CD were seen (right eye to left eye correlation = 0.64); however, a significant difference in variability of endothelial CD between men and women was observed (male: OD, 2839 ± 124 cells/mm² and OS, 2845 ± 124 cells/mm² vs. female: OD, 2838 ± 134 cells/mm² and OS, 2842 ± 132 cells/mm²; OD, P = 0.0013 and OS, P = 0.0016). Eleven individuals were homozygous for the rs613872 risk allele. We found no association between rs613872 genotype and CD or coefficient of variation. One of 11 homozygous GG individuals was found to have a gutta in 1 sample field on specular microscopy, whereas 2 of 297 TT individuals also had a gutta each in 1 sample field. CONCLUSIONS: We were unable to detect an association between TCF4 rs613872 genotype and the variation in corneal endothelial CD or variation in cell morphology in a healthy young adult population.

Incompletely excised skin cancer rates: a prospective study of 31,731 skin cancer excisions by the Western Australian Society of Plastic Surgeons.

BACKGROUND: The incomplete excision of malignant skin lesions is an established measure of the standard of surgical care. It is one of the clinical indicators established by the Royal Australasian College of Surgeons and the Australian Council on Healthcare Standards. PURPOSE OF THE STUDY: The purpose of this study was to identify the rate of incomplete excisions of skin cancers by a group of plastic surgeons in Western Australia and to present the data in a way that enhances the audit process. METHODS: Since 1996, 25 plastic surgeons in Western Australia have been collecting prospective data on incomplete clearances of skin cancer excisions in private practice. A standard data entry form is used and data were collected by clerical staff, independent of the surgeon, and submitted annually to the Western Australian Society of Plastic Surgeons. A lesion was considered to be incompletely excised if tumour was found on histological examination to be present at the excision margin of a specimen. RESULTS: From 1996 to 2002, 25 plastic surgeons performed 31,731 skin lesion excisions over a period of 6 years. Incomplete margins were found on histopathological examination of 1277 lesions (4.02%). Nineteen surgeons performed over 500 procedures. CONCLUSION: The 4.02% rate of incomplete lesion excisions compares favourably to the results of other series. Further development of the audit will yield valuable information on skin lesion management in Western Australia.

Providers and consumers support the Western Australian Audit of Surgical Mortality.

BACKGROUND: The Western Australian Audit of Surgical Mortality (WAASM) was established in June 2001 to independently peer-review all surgical deaths in Western Australia. The objectives of this study were (i) to evaluate whether participation in the WAASM has influenced clinical and hospital practice; and (ii) to ascertain the support and relevance of the WAASM to surgeons, hospitals and consumers. METHODS: Three qualitative questionnaires were designed to evaluate the response of surgeons, hospital administrators and consumers to the WAASM. The outcomes measured included audit participation, value and use of feedback provided, changes to clinical and hospital practice and the future role of the WAASM. RESULTS: The key findings were that 138 (73%) of 190 surgeons participating in the WAASM had changed their clinical practice in at least one way, 44 (24%) were aware of changes in hospital practice and 21 (11%) were aware of changes in a colleague's practice. Particular areas where changes in surgical practice had occurred included attention to deep vein thrombosis prophylaxis (81, 44%), increased constructive discussion among peers (78, 42%) and quality of documentation in case notes (68, 37%). All groups supported the continuation of the WAASM. Hospital executives and consumers recommended that the WAASM be included in accreditation. CONCLUSION: Surgeons, hospitals and consumers supported the concept of independent peer review of surgical care. They confirmed the ability of audit to influence and change surgical and hospital practice. It strengthens the intention of the Royal Australasian College of Surgeons to extend the WAASM project throughout Australia and New Zealand.

The Western Australian Audit of Surgical Mortality: advancing surgical accountability.

OBJECTIVE: To describe the peer review process of the Western Australian Audit of Surgical Mortality (WAASM), selected outcomes and recommendations. STUDY DESIGN: Prospective audit using peer review of all cases of patients who died while under the care of a Western Australian surgeon between 1 January 2002 and 30 June 2004. Audit reviews were current to 30 September 2004. PARTICIPANTS AND SETTING: 194 of 202 surgeons participated after a patient died under their care. MAIN OUTCOME MEASURES: Surgeon participation, deficiencies of care, deep vein thrombosis (DVT) prophylaxis, futile surgery, postmortem reviews, proportion of operations performed by consultant surgeons. RESULTS: The audit process was complete for 896 of 1647 reported deaths (54%), while a further 503 (31%) were still under review at 30 September 2004. Twenty deaths associated with terminal care were excluded from analysis. Median patient age was 80 years, and 799 of the 876 patients who died (91%) had significant comorbidities that increased the risk of death. Deficiencies of care were reported in 179/876 (20%). In 45/876 deaths (5%) the deficiency of care was assessed to have caused the death, and 15 deaths were considered preventable. The risk of a deficiency of care was 1.9 times higher in elective admissions than emergency admissions. Autopsy was undertaken in 83/768 (11%) deaths with complete data. Changes in practice were noted in some areas targeted by WAASM, such as improved DVT prophylaxis. A problem with fluid management was recorded. CONCLUSION: Most patients who died were elderly, had complex comorbidities and were treated appropriately. The WAASM has helped to change surgical practice and emphasises the importance of ongoing systematic audit. The participation of surgeons demonstrates their commitment to accountability and supports the intention of the Royal Australasian College of Surgeons to extend the process throughout Australia and New Zealand.