Runs of homozygosity and testicular cancer risk.

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

Implementing risk-stratified screening for common cancers: a review of potential ethical, legal and social issues.

BACKGROUND: The identification of common genetic variants associated with common cancers including breast, prostate and ovarian cancers would allow population stratification by genotype to effectively target screening and treatment. As scientific, clinical and economic evidence mounts there will be increasing pressure for risk-stratified screening programmes to be implemented. METHODS: This paper reviews some of the main ethical, legal and social issues (ELSI) raised by the introduction of genotyping into risk-stratified screening programmes, in terms of Beauchamp and Childress's four principles of biomedical ethics--respect for autonomy, non-maleficence, beneficence and justice. Two alternative approaches to data collection, storage, communication and consent are used to exemplify the ELSI issues that are likely to be raised. RESULTS: Ultimately, the provision of risk-stratified screening using genotyping raises fundamental questions about respective roles of individuals, healthcare providers and the state in organizing or mandating such programmes, and the principles, which underpin their provision, particularly the requirement for distributive justice. CONCLUSIONS: The scope and breadth of these issues suggest that ELSI relating to risk-stratified screening will become increasingly important for policy-makers, healthcare professionals and a wide diversity of stakeholders.

Public health genomics and personalized prevention: lessons from the COGS project.

Using the principles of public health genomics, we examined the opportunities and challenges of implementing personalized prevention programmes for cancer at the population level. Our model-based estimates indicate that polygenic risk stratification can potentially improve the effectiveness and cost-effectiveness of screening programmes. However, compared with 'one-size-fits-all' screening programmes, personalized screening adds further layers of complexity to the organization of screening services and raises ethical, legal and social challenges. Before polygenic inheritance is translated into population screening strategy, evidence from empirical research and engagement with and education of the public and the health professionals are needed.

Stratified cancer screening: the practicalities of implementation.

BACKGROUND: Improving understanding of the genetic basis of disease susceptibility enables us to estimate individuals' risk of developing cancer and offer them disease prevention, including screening, stratified to reflect that risk. Little attention has so far been given to the implementation of stratified screening. This article reviews the issues that would arise in delivering such tailored approaches to prevention in practice. RESULTS: Issues analysed include the organisational context within which implementation of stratified prevention would occur, how the offer of screening would be made, making sure consent is adequately informed, how individuals' risk would be assessed, the age at which risk estimation should occur, and the potential use of genetic data for other purposes. The review also considers how management might differ depending on individuals' risk, how their results would be communicated and their follow-up arranged, and the different issues raised by modification of an existing screening programme, such as that for breast cancer, and the establishment of a new one, for example for prostate cancer. CONCLUSION: Stratified screening based on genetic testing is a radically new approach to prevention. Various organisational issues would need to be considered before it could be introduced, and a number of questions require further research.

Preconception health care and congenital disorders: mathematical modelling of the impact of a preconception care programme on congenital disorders.

OBJECTIVE: This study aims to model the impact of preconception care on births with congenital disorders at a national level. DESIGN: Mathematical cross-sectional model based on life-table methodology. SETTING: Research conducted in Cambridge, United Kingdom. POPULATION: Women aged 15-45 years in England, 2001. METHODS: A mathematical model was constructed based on cross-sectional data from women aged 15-45 years in England undertaking one of three interventions, so as to reflect different strategies of preconception care: folic acid supplementation and fortification (representing national, universal interventions); alcohol intervention (reflecting primary care strategies); and diabetes management (targeting a population of high-risk women with a known chronic disease). MAIN OUTCOME MEASURE: Reduction in the prevalence of congenital disorders at birth. RESULTS: Between 585 (lower estimate) and 1085 (upper estimate) congenital disorders could be prevented with a national preconception programme, based on a single-year national cohort in England. This represents an 8-15% reduction in annual notifications of congenital disorders in live births annually. According to modelled estimates, folic acid fortification or supplementation, alcohol intervention, and diabetic management may result in a 46, 32-62, 53, and 54% reduction in the live birth prevalence of specific congenital disorders, respectively. In an ideal scenario, the application of this model decreases the total annual number of congenital disorder notifications by approximately one-sixth. CONCLUSION: A preconception care programme comprising three different strategies potentially can reduce the number of infants born with congenital disorders at a national level. This model provides strong support for preconception care to become a healthcare priority, and has major implications for healthcare planning.

Burden of disease due to cancer in England and Wales.

BACKGROUND: This study aims to estimate the burden of cancer in England and Wales using disability-adjusted life years (DALYs) and to determine if the ranking of relative importance changes with metric used. METHODS: DALYs are the sum of years of life lost due to mortality and years lost due to disability. Annual DALYs due to cancer were calculated using cancer registration, mortality, disability weights and World Health Organization methodology. RESULTS: There were 8 605 362 DALYs due to cancer (3242 DALYs/100 000 population/year). Of the total, 47% corresponded to lung, prostate and colorectal cancers in males and 56% to breast, lung, colorectal and ovarian cancers in females. Mortality (86% of DALYs) contributed predominantly to DALYs. Individuals of 65-75 years contributed to 28% of DALYs. Among females, lung cancer ranked highest by death rates, whereas the highest DALYs were from breast cancer. CONCLUSIONS: Highest DALYs were due to lung, breast, prostate and colorectal cancers in England and Wales. The addition of the disability component changes the relative position of some of the top cancers. Although metrics based on deaths alone capture most effects of cancer on population health levels, important additional perspectives, relevant to the planning of services, can be gained from burden of disease analyses.

Polygenic susceptibility to prostate and breast cancer: implications for personalised screening.

BACKGROUND: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone. METHODS: We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively). RESULTS: Compared with screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases. CONCLUSION: Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.

Mean sojourn time, overdiagnosis, and reduction in advanced stage prostate cancer due to screening with PSA: implications of sojourn time on screening.

This study aimed to assess the mean sojourn time (MST) of prostate cancer, to estimate the probability of overdiagnosis, and to predict the potential reduction in advanced stage disease due to screening with PSA. The MST of prostate cancer was derived from detection rates at PSA prevalence testing in 43,842 men, aged 50-69 years, as part of the ProtecT study, from the incidence of non-screen-detected cases obtained from the English population-based cancer registry database, and from PSA sensitivity obtained from the medical literature. The relative reduction in advanced stage disease was derived from the expected and observed incidences of advanced stage prostate cancer. The age-specific MST for men aged 50-59 and 60-69 years were 11.3 and 12.6 years, respectively. Overdiagnosis estimates increased with age; 10-31% of the PSA-detected cases were estimated to be overdiagnosed. An interscreening interval of 2 years was predicted to result in 37 and 63% reduction in advanced stage disease in men 65-69 and 50-54 years, respectively. If the overdiagnosed cases were excluded, the estimated reductions were 9 and 54%, respectively. Thus, the benefit of screening in reducing advanced stage disease is limited by overdiagnosis, which is greater in older men.

Survival trends for small intestinal cancer in England and Wales, 1971-1990: national population-based study.

This population-based study examines prognostic factors and survival trends among adults (15-99 years) diagnosed with small intestinal cancer in England and Wales during 1971-1990 and followed up to 1995. During this period, the 1- and 5-year age-standardised relative survival rates for small intestinal cancers combined were 42% and 23%, respectively. Duodenal tumours, adenocarcinomas, men, patients with advanced age and the most deprived patients had the poorest prognosis. For all small bowel tumours combined, the excess risk of death fell significantly by 6-9% every 4 years over the 20-year period (adjusted excess hazard ratio (EHR) 0.91 at 1 year after diagnosis, 0.94 at 5 years). For duodenal tumours, the EHR fell by about 14% (95% CI 5-22%) every 4 years between 1979 and 1990, and a similar trend for jejunal tumours was of borderline significance. Further population-based investigations linking survival data to individual data on diagnostic methods and types of treatment are needed.

Excess cases of prostate cancer and estimated overdiagnosis associated with PSA testing in East Anglia.

This study aimed to estimate the extent of 'overdiagnosis' of prostate cancer attributable to prostate-specific antigen (PSA) testing in the Cambridge area between 1996 and 2002. Overdiagnosis was defined conceptually as detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient's lifetime. Records of PSA tests in Addenbrookes Hospital were linked to prostate cancer registrations by NHS number. Differences in prostate cancer registration rates between those receiving and not receiving prediagnosis PSA tests were calculated. The proportion of men aged 40 years or over with a prediagnosis PSA test increased from 1.4 to 5.2% from 1996 to 2002. The rate of diagnosis of prostate cancer was 45% higher (rate ratios (RR)=1.45, 95% confidence intervals (CI) 1.02-2.07) in men with a history of prediagnosis PSA testing. Assuming average lead times of 5-10 years, 40-98% [corrected] of the PSA-detected cases were estimated to be overdiagnosed. In East Anglia, from 1996 to 2000, a 1.6% excess of cases was associated with PSA testing (around a quarter of the 5.3% excess incidence cases observed in East Anglia from 1996 to 2000). Further quantification of the overdiagnosis will result from continued surveillance and from linkage of incidence to testing in other hospitals.

Incidence trends of prostate cancer in East Anglia, before and during the era of PSA diagnostic testing.

We investigated prostate cancer incidence in East Anglia from 1971 to 2000. Using age-period-cohort modelling, the number of cases expected in 1991-2000, based on pre-PSA trends, 1971-1990, was compared with that observed. Based on pre-1991 trends, 9203 new cases were expected in 1991-2000, but 9788 cases were observed, an excess of 6%.

Practice patterns of antiphospholipid syndrome at a tertiary teaching hospital in Lebanon.

The objective of the study was to describe the practice patterns of the antiphospholipid syndrome (APS) as compared with consensus guidelines for diagnosis and to determine whether practice patterns correlate with patient demographics and physician specialty. A retrospective medical chart review was conducted at the American University Hospital, in Beirut, Lebanon. All adult and pediatric patients admitted to the hospital between 1 January and 31 December 1998 who underwent either anticardiolipin antibodies (aCL) or lupus anticoagulant (LA) testing were included in the study. Work-up of APS syndrome was compared with: (a) the consensus guidelines for clinical diagnosis; (b) physician specialty; and (c) patient demographics (age, gender, ethnicity, health insurance status). Eighty-seven patients fulfilled at least one clinical criterion for APS; 92% were for work-up of thrombosis and 8% for pregnancy morbidities. Fifty-one percent underwent both aCL and LA. Overall 38% (33) of patients had an abnormal test result, however only 18% (6) underwent retesting, of whom only two satisfied a minimum of 6 weeks between test and retest TheAPS diagnostic work-up was requested by 11 different specialties. Rheumatologists were the most consistent in asking for both tests. APS is seen and diagnosed by a variety of medical specialties. Practice patterns as compared with the latest consensus are sub-optimal, and need to be improved. Interventions to help improve this have been discussed and are being implemented.

Routine urinalysis of patients in hospital in Lebanon: how worthwhile is it?

OBJECTIVES: To examine the impact of routine urinalysis at admission on inpatient care at a hospital in Lebanon, where physicians perceive it to be a valuable diagnostic tool, in a country where preventive services are underdeveloped and where the epidemiology of kidney diseases possibly differs from that of the western world. SETTING: American University Hospital, a tertiary teaching hospital in Beirut, Lebanon. METHODS: A retrospective medical record review of all adult patients admitted over 2 weeks to the medicine and surgery wards of the American University Hospital. Outcomes measured were frequency of routine urinalysis versus urinalysis for a clinical indication, investigation of abnormal test results, and implications of test results on clinical management. RESULTS: 367 (79%) of 462 study patients underwent urinalysis. 266 (73%) patients had routine urinalysis. Abnormal results were found in 97(37%) routine tests and 67 (66%) of those clinically indicated urinalysis (p<0.001). Abnormalities were investigated in 21 (22%) of the abnormal routine urinalyses and 45 (67%) of the abnormal clinically indicated urinalyses (p<0.001). Logistic regression analysis showed no factors to correlate positively with investigation of abnormal urinalysis. Treatment was given to two (1%) patients who had had routine urinalysis and 26 (26%) of all those tested because of a clinical indication (p<0.001). CONCLUSIONS: Clinical response to any abnormal urinalysis is more likely when a urine test is done for a clinical indication. In this study setting, impact of routine admission urinalysis on patient care was negligible. Despite physicians' perception of routine urinalysis being a valuable case finding tool, in this study its true value remains questionable.