Forecasting age-specific breast cancer mortality using functional data models

Accurate estimates of future age-specific incidence and mortality are critical for allocation of resources to breast cancer control programs and evaluation of screening programs. The purpose of this study is to apply functional data analysis techniques to model age-specific breast cancer mortality time trends, and forecast entire age-specific mortality function using a state-space approach. We use yearly unadjusted breast cancer mortality rates in Australia, from 1921 to 2001 in 5 year age groups (45 to 85+). We use functional data analysis techniques where mortality and incidence are modeled as curves with age as a functional covariate varying by time. Data is smoothed using nonparametric smoothing methods then decomposed (using principal components analysis) to estimate basis functions that represent the functional curve. Period effects from the fitted functions are forecast then multiplied by the basis functions, resulting in a forecast mortality curve with prediction intervals. To forecast, we adopt a state-space approach and an extension of the Pegels modeling framework for selecting among exponential smoothing methods. Overall, breast cancer mortality rates in Australia remained relatively stable from 1960 to the late 1990's but declined over the last few years. A set of K=4 basis functions minimized the mean integrated squared forecasting error (MISFE) and accounts for 99.3% of variation around the mean mortality curve. 20 year forecast suggest a continual decline at a slower rate and stabilize beyond 2010 and by age, forecasts show a decline in all age groups with the greatest decline in older women. We illustrate the utility of a new modelling and forecasting approach to model breast cancer mortality rates using a functional model of age. The methods have the potential to incorporate important covariates such as Hormone Replacement Therapy (HRT) and interventions to represent mammographic screening. This would be particularly useful for evaluating the impact of screening on mortality and incidence from breast cancer.Mortality, Breast Cancer, Forecasting, Functional Data Analysis, Exponential Smoothing

Effectiveness of less than three doses of quadrivalent human papillomavirus vaccine against cervical intraepithelial neoplasia when administered using a standard dose spacing schedule: Observational cohort of young women in Australia

AbstractBackgroundOptimised two-dose human papillomavirus (HPV) vaccine schedules are now endorsed for young adolescents by the World Health Organization. Limited data are available about effectiveness of <3 doses using a standard dose schedule.MethodsDeterministic data linkage was undertaken between the Victorian Cervical Cytology Registry and National HPV Vaccination Program Register to determine quadrivalent HPV vaccination status and incidence of cervical pathology among vaccine eligible women (aged 26 years or younger in 2007) screened in Victoria, Australia between April 2007 and December 2011. Proportional hazards regression was used to estimate hazard ratios (HR) adjusted for age, socioeconomic status and area of residence. Women were stratified into those vaccinated before or after first screen.ResultsAny number of doses (1, 2 or 3) were associated with lower rates of high grade and low grade cytology diagnoses as long as doses were given before screening commencement (one dose HR high grade 0.44 (95% CI 0.32–0.59), one dose low grade 0.48 (95% CI 0.40–0.58); two doses HR high grade 0.63 (95% CI 0.50–0.80), HR low grade 0.52 (95% CI 0.44–0.61); three doses HR high grade 0.53 (95% CI 0.47–0.60), HR low grade 0.73 (95% CI 0.68–0.78)). Three doses of vaccine, but not fewer, were associated with reduced risk of high grade histologically confirmed abnormality in this cohort, regardless of whether vaccination occurred before or after screening (HR before 0.71 (95% CI 0.64–0.80), HR after 0.87 (95% CI 0.82–0.93)). Secondary analyses censoring end points occurring within 1, 6, 12, or 24 months of final vaccine dose suggested an increasing effect of partial vaccination courses over time.ConclusionOur data suggest that less than three doses of quadrivalent HPV vaccine provides some protection against cervical intraepithelial neoplasia, even when measured within 5 years in a population including those who were sexually active at the time of vaccination

The AIB1 glutamine repeat polymorphism is not associated with risk of breast cancer before age 40 years in Australian women

INTRODUCTION: AIB1, located at 20q12, is a member of the steroid hormone coactivator family. It contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer through altered sensitivity to hormones. METHODS: We evaluated this repeat polymorphism in the context of early-onset disease by conducting a case-control study of 432 Australian women diagnosed with breast cancer before the age of 40 years and 393 population-based control individuals who were frequency matched for age. Genotyping was performed using a scanning laser fluorescence imager. RESULTS: There were no differences in genotype frequencies between cases and control individuals, or between cases categorized by family history or by BRCA1 and BRCA2 germline mutation status. There was no evidence that the presence of one or two alleles of 26 glutamine repeats or fewer was associated with breast cancer (odds ratio = 1.03, 95% confidence interval = 0.73–1.44), or that women with alleles greater than 29 repeats were at increased risk of breast cancer. Exclusion of women who carried a BRCA1 or BRCA2 mutation (24 cases) and non-Caucasian women (44 cases) did not alter the risk estimates or inferences. We present raw data, including that on mutation carriers, to allow pooling with other studies. CONCLUSION: There was no evidence that risk of breast cancer depends on AIB1 CAG/CAA polymorphism status, even if affected women carry a mutation in BRCA1 or BRCA2

SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis

<p>Abstract</p> <p>Background</p> <p>We report our experience of selecting tag SNPs in 35 genes involved in iron metabolism in a cohort study seeking to discover genetic modifiers of hereditary hemochromatosis.</p> <p>Methods</p> <p>We combined our own and publicly available resequencing data with HapMap to maximise our coverage to select 384 SNPs in candidate genes suitable for typing on the Illumina platform.</p> <p>Results</p> <p>Validation/design scores above 0.6 were not strongly correlated with SNP performance as estimated by Gentrain score. We contrasted results from two tag SNP selection algorithms, LDselect and Tagger. Varying r²from 0.5 to 1.0 produced a near linear correlation with the number of tag SNPs required. We examined the pattern of linkage disequilibrium of three levels of resequencing coverage for the transferrin gene and found HapMap phase 1 tag SNPs capture 45% of the ≥ 3% MAF SNPs found in SeattleSNPs where there is nearly complete resequencing. Resequencing can reveal adjacent SNPs (within 60 bp) which may affect assay performance. We report the number of SNPs present within the region of six of our larger candidate genes, for different versions of stock genotyping assays.</p> <p>Conclusion</p> <p>A candidate gene approach should seek to maximise coverage, and this can be improved by adding to HapMap data any available sequencing data. Tag SNP software must be fast and flexible to data changes, since tag SNP selection involves iteration as investigators seek to satisfy the competing demands of coverage within and between populations, and typability on the technology platform chosen.</p

Iron-overload-related disease in HFE hereditary hemochromatosis

Background: Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial. Methods: We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. Results: The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1000 μg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene. Conclusions: In persons who are homozygous for the C282Y mutation, iron-overload-related disease developed in a substantial proportion of men but in a small proportion of women

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors: Australian Breast Cancer Family Study

INTRODUCTION: Because CYP17 can influence the degree of exposure of breast tissues to oestrogen, the interaction between polymorphisms in this gene and hormonal risk factors is of particular interest. We attempted to replicate the findings of studies assessing such interactions with the -34T→C polymorphism. METHODS: Risk factor and CYP17 genotyping data were derived from a large Australian population-based case-control-family study of 1,284 breast cancer cases and 679 controls. Crude and adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses. RESULTS: We found no associations between the CYP17 genotype and breast cancer overall. Premenopausal controls with A(2)/A(2 )genotype had a later age at menarche (P < 0.01). The only associations near statistical significance were that postmenopausal women with A(1)/A(1 )(wild-type) genotype had an increased risk of breast cancer if they had ever used hormone replacement therapy (OR 2.40, 95% CI 1.0 to 5.7; P = 0.05) and if they had menopause after age 47 years (OR 2.59, 95% CI 1.0 to 7.0; P = 0.06). We found no associations in common with any other studies, and no evidence for interactions. CONCLUSION: We observed no evidence of effect modification of reproductive risk factors by CYP17 genotype, although the experiment did not have sufficient statistical power to detect small main effects and modest effects in subgroups. Associations found only in subgroup analyses based on relatively small numbers require cautious interpretation without confirmation by other studies. This emphasizes the need for replication in multiple and large population-based studies to provide convincing evidence for gene–environment interactions

Public health aspects of genetic screening for hereditary haemochromatosis in Australia

Abstract Hereditary haemochromatosis (HH) is an inherited disorder of iron absorption. It meets several of the key public health principles for population‐based screening and is considered to be a test‐case for public health genetics However, there has been relatively little debate in the public health or wider community regarding the merits of population‐based genetic screening for HH. Genetic susceptibility to HH occurs in about 1:200 people and although mortality is low (age‐standardised rate 2.75/million), there are potentially serious clinical manifestations of iron overload. Regular venesection is a simple and effective treatment for early stage iron overload. DNA‐based testing is available and iron overload may be identified using serum transferrin saturation and ferritin tests. However, there are important gaps in knowledge relevant to screening for HH. The limited data on penetrance of HFE genotypes, and thus the uncertain probability that genetically susceptible individuals will develop clinically significant disease, is a major impediment to population‐based genetic screening. Clinical evidence supports treating early‐stage disease but no randomised controlled trials of the effectiveness of screening in reducing the burden of disease have been conducted. In addition, the natural history of early stages of HH and factors that may modify progression are unclear. Two international consensus panels on HH concluded that there is insufficient evidence for population‐based screening at present. We present recommendations to advance the debate on screening for HH in Australia