The ORNATE India Project: United Kingdom-India Research Collaboration to tackle visual impairment due to diabetic retinopathy.

INTRODUCTION: The ORNATE India project is funded by the UK Research and Innovation (UKRI) through the Global Challenges Research Fund. The aim is to build research capacity and capability in India and the UK to tackle global burden of diabetes-related visual impairment. As there are over 77 million people with diabetes in India, it is challenging to screen every person with diabetes annually for sight-threatening diabetic retinopathy (DR). Therefore, alternate safe approaches need to be developed so that those at-risk of visual impairment due to DR is identified promptly and treated. METHODS: The project team utilised diverse global health strategies and research methods to co-design work packages to build research capacity and capability to ensure effective, affordable and efficient DR services are made available for the population. The strategies and methods employed included health system strengthening; implementation science; establishing care pathways; co-designing collaborative studies on affordable technologies, developing quality standards and guidelines to decrease variations in care; economic analysis; risk modelling and stratification. Five integrated work packages have been developed to deal with all aspects of DR care. These included implementation of a DR screening programme in the public health system in a district in Kerala, evaluating regional prevalence of diabetes and DR and assessing ideal tests for holistic screening for diabetes and its complications in 20 areas in India, utilising artificial intelligence on retinal images to facilitate DR screening, exploring biomarker and biosensor research to detect people at risk of diabetes complications, estimating cost of blindness in India and risk modelling to develop risk-based screening models for diabetes and its complications. A large collaborative network will be formed to propagate research, promote shared learning and bilateral exchanges between high- and middle-income countries to tackle diabetes-related blindness.

Managing uncertain recovery for patients nearing the end of life in hospital: a mixed-methods feasibility cluster randomised controlled trial of the AMBER care bundle.

BACKGROUND: The AMBER (Assessment, Management, Best Practice, Engagement, Recovery Uncertain) care bundle is a complex intervention used in UK hospitals to support patients with uncertain recovery. However, it has yet to be evaluated in a randomised controlled trial (RCT) to identify potential benefits or harms. The aim of this trial was to investigate the feasibility of a cluster RCT of the AMBER care bundle. METHODS: This is a prospective mixed-methods feasibility cluster RCT. Quantitative data collected from patients (or proxies if patients lack capacity) were used (i) to examine recruitment, retention and follow-up rates; (ii) to test data collection tools for the trial and determine their optimum timing; (iii) to test methods to identify the use of financial resources; and (iv) to explore the acceptability of study procedures for health professionals and patients. Descriptive statistical analyses and thematic analysis used the framework approach. RESULTS: In total, 894 patients were screened, of whom 220 were eligible and 19 of those eligible (8.6%) declined to participate. Recruitment to the control arm was challenging. Of the 728 patients screened for that arm, 647 (88.9%) were excluded. Overall, 65 patients were recruited (81.3% of the recruitment target of 80). Overall, many were elderly (≥80 years, 46.2%, n = 30, mean = 77.8 years, standard deviation [SD] = 12.3 years). Over half (53.8%) had a non-cancer diagnosis, with a mean of 2.3 co-morbidities; 24.6% patients (n = 16) died during their hospital stay and 35.4% (n = 23) within 100 days of discharge. In both trial arms, baseline IPOS subscale scores identified moderate patient anxiety (control: mean 13.3, SD 4.8; intervention: mean 13.3, SD 5.1), and howRwe identified a good care experience (control: mean 13.1, SD 2.5; intervention: mean 11.5, SD 2.1). Collecting quantitative service use and quality of life data was feasible. No patient participants regarded study involvement negatively. Focus groups with health professionals identified concerns regarding (i) the subjectivity of the intervention's eligibility criteria, (ii) the need to prognosticate to identify potential patients and (iii) consent procedures and the length of the questionnaire. CONCLUSIONS: A full trial of the AMBER care bundle is technically feasible but impractical due to fundamental issues in operationalising the intervention's eligibility criteria, which prevents optimal recruitment. Since this complex intervention continues to be used in clinical care and advocated in policy, alternative research approaches must be considered and tested. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) Register, ISRCTN36040085 .

Vascular invasion in hepatocellular carcinoma: is there a correlation with MRI?

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the commonest malignancies worldwide. Prognosis is predicted by size at diagnosis, vascular invasion and tumour proliferation markers. This study investigates if MRI features of histologically proven HCCs correlate with vascular invasion. METHODS: Between 2006 and 2008, 18 consecutive patients, with a total of 27 HCCs, had comprehensive MRI studies performed at our institution within a median of 36 days of histology sampling. Each lesion was evaluated independently on MRI by 3 radiologists (blinded to both the radiology and histopathology reports) using a 5-point confidence scale for 23 specific imaging features. The mean of the rating scores across readers was calculated to determine interobserver consistency. The most consistent features were then used to examine the value of features in predicting vascular invasion, using a χ(2 )test for trend, having eliminated those features without sufficient variability. RESULTS: 22 of the 23 imaging features showed sufficient variability across lesions. None of these significantly correlated with the presence of vascular invasion, although a trend was identified with the presence of washout in the portal venous phase on MRI and the median size of lesions, which was greater with vascular invasion. CONCLUSION: This study suggests that no single MRI feature accurately predicts the presence of vascular invasion in HCCs, although a trend was seen with the presence of washout in the portal venous phase post gadolinium. Larger prospective studies are required to investigate this further.

Diagnosis of prostate cancer by detection of minichromosome maintenance 5 protein in urine sediments.

BACKGROUND: The accuracy of prostate-specific antigen (PSA) testing in prostate cancer detection is constrained by low sensitivity and specificity. Dysregulated expression of minichromosome maintenance (Mcm) 2-7 proteins is an early event in epithelial multistep carcinogenesis and thus MCM proteins represent powerful cancer diagnostic markers. In this study we investigate Mcm5 as a urinary biomarker for prostate cancer detection. METHODS: Urine was obtained from 88 men with prostate cancer and from two control groups negative for malignancy. A strictly normal cohort included 28 men with complete, normal investigations, no urinary calculi and serum PSA <2 ng ml(-1). An expanded control cohort comprised 331 men with a benign final diagnosis, regardless of PSA level. Urine was collected before and after prostate massage in the cancer patient cohort. An immunofluorometric assay was used to measure Mcm5 levels in urine sediments. RESULTS: The Mcm5 test detected prostate cancer with 82% sensitivity (confidence interval (CI)= 72-89%) and with a specificity ranging from 73 (CI=68-78%) to 93% (CI=76-99%). Prostate massage led to increased Mcm5 signals compared with pre-massage samples (median 3440 (interquartile range (IQR) 2280 to 5220) vs 2360 (IQR <1800 to 4360); P=0.009), and was associated with significantly increased diagnostic sensitivity (82 vs 60%; P=0.012). CONCLUSIONS: Urinary Mcm5 detection seems to be a simple, accurate and noninvasive method for identifying patients with prostate cancer. Large-scale prospective trials are now required to evaluate this test in diagnosis and screening.

Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer.

Multiparameter analysis of core regulatory proteins involved in G1-S and G2-M cell-cycle transitions provides a powerful biomarker readout for assessment of the cell-cycle state. We have applied this algorithm to breast cancer to investigate how the cell cycle impacts on disease progression. Protein expression profiles of key constituents of the DNA replication licensing pathway (Mcm2, geminin) and mitotic machinery (Plk1, Aurora A and the Aurora substrate histone H3S10ph) were generated for a cohort of 182 patients and linked to clinicopathological parameters. Arrested differentiation and genomic instability were associated with an increased engagement of cells into the cell division cycle (P<0.0001). Three unique cell-cycle phenotypes were identified: (1) well-differentiated tumours composed predominantly of Mcm2-negative cells, indicative of an out-of-cycle state (18% of cases); (2) high Mcm2-expressing tumours but with low geminin, Aurora A, Plk1 and H3S10ph levels (S-G2-M progression markers), indicative of a G1-delayed/arrested state (24% cases); and (3) high Mcm2-expressing tumours and also expressing high levels of the S-G2-M progression markers, indicative of accelerated cell-cycle progression (58% of cases). The active cell-cycle progression phenotype had a higher risk of relapse when compared with out-of-cycle and G1-delayed/arrested phenotypes (HR=3.90 (1.81-8.40, P<0.001)), and was associated with Her-2 and triple negative subtypes (P<0.001). It is of note that high-grade tumours with the G1-delayed/arrested phenotype showed an identical low risk of relapse compared with well-differentiated out-of-cycle tumours (HR=1.00 (0.22-4.46), P=0.99). Our biomarker algorithm provides novel insights into the cell-cycle state of dynamic tumour cell populations in vivo. This information is of major prognostic significance and may impact on individualised therapeutic decisions. Patients with an accelerated phenotype are more likely to derive benefit from S- and M-phase-directed chemotherapeutic agents.

Randomization at the level of primary care practice: use of pre-intervention data and random effects models.

The Anglia menorrhagia education study tests the effectiveness of an education package for the treatment of menorrhagia given to doctors at a primary care level. General practices were randomized to receive or not receive the package. It is hoped that this intervention will reduce the proportion of women suffering from menorrhagia that are referred to hospital. Data are available on the treatment and referral of women in the practices in the education and control groups, both pre- and post-intervention. We define and demonstrate a random effects logistic regression model that includes pre-intervention data for calculating the effectiveness of the intervention.

Hierarchical models in generalized synthesis of evidence: an example based on studies of breast cancer screening.

Evidence regarding the potential benefits of a particular health care intervention is often available from a variety of disparate sources. However, formal synthesis of such evidence has traditionally concentrated almost exclusively on that derived from randomized studies, although for a range of conditions the randomized evidence will be less than adequate due to economic, organizational or ethical considerations. In such situations a formal synthesis of the evidence that is available from observational studies can be valuable whilst awaiting higher quality evidence from randomized trials. Consideration of randomized studies alone may be appropriate when assessing the efficacy of an intervention, but assessment of the effectiveness of such an intervention within a more general target population may be improved by consideration of evidence from non-randomized studies as well. Standard meta-analysis methods may allow for both within- and between-study heterogeneity; however when multiple sources of evidence are considered an extra level of complexity is introduced, namely study type. One possible solution to the problem of making inferences, particularly regarding an overall population effect, in such situations is to model the heterogeneity, both quantitative and qualitative, using a Bayesian hierarchical model. The hierarchical nature of such models specifically allows for the quantitative within and between sources of heterogeneity, whilst the Bayesian approach can accommodate a priori beliefs regarding qualitative differences between the various sources of evidence. The use of such methods in practice is illustrated in the context of screening for breast cancer; in this example evidence is available from both randomized clinical trials and observational studies. A particular appeal of a Bayesian approach for this type of problem lies in the prediction of future benefits likely to be observed in a target population. This approach to health service monitoring in general is discussed.

Mammographic screening in women with a family history of breast cancer: some results from the Swedish two-county trial.

BACKGROUND: The objective of this study is to compare the effectiveness of mammographic screening in women with a family history of breast cancer to those without. In the invited arm of a randomised trial of breast cancer screening, data on family history of breast cancer were available on 29.179 women aged 40-74 attending for screening. Among those women, 358 were diagnosed with breast cancer during the trial. METHODS: Those with and without a family history were compared with respect to mammographic parenchymal pattern, interval cancer rates, mean sojourn time and sensitivity of screening. In the 358 cancers, the effect of family history was estimated on survival, incidence of advanced cancers and their relationship to screen detection. RESULTS: A significantly higher proportion of high risk mammographic patterns was observed in association with family history among women aged 40-49. Interval cancer rates were higher in women with a family history, and in older women at least, mean sojourn time was shortened in women with a family history (1.89 years compared to 2.70). Survival was better (although not significantly so) in cancers in women with a family history (relative hazard=0.52) independently of detection mode and was significantly poorer in interval cancers then screen detected cancers (relative hazard=2.72) independently of family history. Similarly, interval cancers tended to be larger, and worse malignancy grade in those with and without a family history of breast cancer. CONCLUSIONS: These results suggest that the policy often adopted of annual screening for woman aged 40-49, with a family history of breast cancer, is a reasonable one, and that it may also be necessary to shorten the inter-screening interval to one year in women aged over 50 but with a positive family history.

The Huntingdon Day Hospital Trial: secondary outcome measures.

OBJECTIVE: To compare day hospital to day centre rehabilitation using scales to measure mobility, activities of daily living and quality of life. DESIGN: Single blind randomized controlled trial with home assessments at baseline (twice), six weeks and three months. SETTING: Mainly rural health district. Day hospital and social services day centres in market towns. INTERVENTIONS: Day hospital treatment or day centre rehabilitation by a physiotherapist and two health support workers. MAIN OUTCOME MEASURES: World Health Organization mobility scale scored with and without aid, Nottingham Extended Activities of Daily Living Scale and Nottingham Health Profile. SUBJECTS: One hundred and five physically disabled older patients living at home referred for day hospital rehabilitation or maintenance before discharge from hospital (66) or referred as outpatients (39). RESULTS: At three months there were no statistically significant differences between rehabilitation at day hospital and day centre for any of the outcome measurements. However, there were significant improvements between baseline and three months for the following subscales [mean change per six-week period (95% confidence interval) ]: WHO mobility subscale (with aid) -0.67 (-0.99,-0.35); Nottingham Health Profile mobility subscale -10 (-15.5,-4.5) Nottingham extended ADL mobility subscale +3.08 (1.78,4.37); Nottingham extended ADL leisure subscale +1.66 (0.96,2.36). CONCLUSION: There were no differences between day hospital and day centre in the outcomes measured. Day rehabilitation appeared to improve functional ability and mobility and scales reflecting these domains deserve further evaluation as outcome measures in this patient group. However, no improvement in quality of life was observed.

Variation in the interaction between familial and reproductive factors on the risk of breast cancer according to age, menopausal status, and degree of familiality.

BACKGROUND: Studies have found that reproductive factors might have a variable effect on the occurrence of breast cancer (BC) according to the existence or not of a family history of BC. The effect of a family history of BC on the risk of BC may also vary according to the age at diagnosis and the degree of kinship. This may confound the relation between familial risk and reproductive factors. A combined analysis was performed to study the interaction between familial risk and reproductive factors according to degree of familiality, age at interview and menopausal status. METHODS: The present analysis included 2948 cases and 4170 controls in seven case-control studies from four countries. The combined relative risks were estimated using a Bayesian random-effects logistic regression model. RESULTS: The main effects of reproductive life factors on the risk of BC are in agreement with previous studies. Two-way interactions between subject's age or menopausal status and a family history of BC were not significant. Although the three-way interaction between age, familial risk and parity was not significant, familial risk seemed to be increased slightly for women with high parity compared with women with low parity in the older age group, and seemed to be slightly decreased for women with high parity compared with women with low parity in younger women. The subject's age also appeared to have an effect on the interaction between familial risk and the age at first childbirth (P = 0.1). CONCLUSIONS: A possible influence of reproductive and menstrual factors on familial risk of BC has been suggested previously and was also evident in the present study. Three-way interactions between age, family history and parity or age at first childbirth might exist and they merit further investigation.

Some random-effects models for the analysis of matched-cluster randomised trials: application to the Swedish two-county trial of breast-cancer screening.

BACKGROUND: In the Swedish two-county trial women aged 40-74 years from two counties in Sweden were randomised to invitation to mammographic screening for breast cancer. METHODS: This paper uses random effects logistic regression models to analyse recent data from the trial. The analysis accounts for the structure of the trial, where small geographical units are randomised within larger geographical strata (blocks of two or three small units that are socio-economically similar). RESULTS: Fixed effects and a variety of random effects models show a strong degree of agreement and yield a significant 29% or 30% reduction in breast-cancer mortality. DISCUSSION: Fixed effects and random effects models agree for this example, because heterogeneity both between strata and within strata between clusters is small and because the effect of treatment does not vary much in different strata.

Use of person-years of CIN III exposure as a surrogate outcome measure in cervical cancer screening trials.

BACKGROUND: The reluctance to perform randomised trials on still unresolved issues of the cervical screening programme is largely due to the view that using invasive cancer as an end-point would require huge and lengthy studies. However, by assuming that the incidence of invasive cancer is related to the number of women with CIN III, an estimate of person-years of CIN III can act as a surrogate outcome. METHODS: By having a reliable model for the development of CIN III and the errors involved in taking the smears and biopsies, the person-years of CIN III can be estimated from a smear and biopsy history. Methods for comparing resulting distributions of person-years of CIN III are discussed. Sensitivity analyses on the error rates of smear and biopsy results, and on the incidence of onset and regression of CIN III are performed. RESULTS: Estimates of person-years of CIN III were calculated for women with mildly abnormal smears in two screening programmes. 11% of women in the Cambridge programme and 21% in the Aberdeen programme were estimated to have been exposed to CIN III for more than 12 months. The greater estimated person-years of CIN III in the Aberdeen study reflects the more conservative treatment policy which was operating there. DISCUSSION: The use of person-years of CIN III as a surrogate outcome can provide a practical and meaningful assessment of strategies for cervical cancer screening. Using CIN III, in place of invasive disease, considerably reduces the study duration and sample size required.

Update of the Swedish Two-County Trial of breast cancer screening: histologic grade-specific and age-specific results.

UNLABELLED: The benefit of mammographic screening in reducing mortality from breast cancer is well established. Questions remain with respect to the magnitude of the long-term benefit of modern mammography screening, age specific benefits and the timing of these, and histology specific effects. METHODS: The Swedish Two-County Trial was set up in 1977, with 77,080 women aged 40-74 randomised to invitation to mammographic screening for breast cancer (active study population, ASP) and 55,985 women randomised to no invitation (passive study population, PSP). There is now follow-up for mortality to 31 December 1996, approximately 18 years average follow-up. We investigated the effect of invitation of screening on breast cancer mortality and incidence of advanced tumours by age group (40-49 and 50-74) and histologic type. In addition we estimated progression rates by histologic grade using markov chain models. RESULTS: A significant 29% reduction in breast cancer mortality was observed in association with invitation to screening (relative risk = 0.71, 95% confidence interval 0.60-0.83), maintaining the effect observed at previous stages of follow-up. Age-specific analyses show a smaller and later mortality benefit in women aged 40-49. This is related to the fact that there is a considerable benefit from early detection in terms of mortality from aggressive, poorly differentiated cancers in women aged 50-74, whereas the major effect in women aged 40-49 is on the less aggressive tumours of good or intermediate differentiation. Among women aged 50-74, the incidence of grade III tumours in the ASP is significantly lower than in the PSP, but this is not the case for women aged 40-49. This is related to the greater prevalence and rapidity of progression with respect to histologic grade, as evidenced by the results of markov chain models and the proportions of grade III tumours by time since last screen. CONCLUSIONS: The substantial and significant mortality benefit of invitation to mammographic screening in women aged 40-74 is maintained at 18 years of follow-up. To achieve a substantial mortality benefit at an early stage in the screening program in women aged under 50 years, an interscreening interval of 12-18 months would be required.

Evaluation of a selective screening for colorectal carcinoma: the Taiwan Multicenter Cancer Screening (TAMCAS) project.

BACKGROUND: Although the efficacy of mass screening for colorectal carcinoma (CRC) with a fecal occult blood test has been demonstrated in several randomized trials, a mass screening approach used in countries with intermediate or low incidence of CRC might be costly. Screening high risk people may be an alternative approach, to aid in the prevention of death from CRC. However, the efficacy of CRC screening for high risk people in such countries is uncertain. METHODS: For this study, a multicenter design was devised to identify high risk groups without clinical symptoms related to CRC; these subjects were identified through the study of index cases of CRC in Taiwan. Colonoscopy, in combination with a fecal occult blood test or double-contrast barium enema, was used to screen high risk groups. A total of 8909 subjects were invited to attend screening. Of 8909, 81 with asymptomatic CRC were detected in one-shot screening. Markov models, in conjunction with a simulated approach, were proposed to estimate relevant parameters in relation to disease progression and to assess the effect of the interval between screenings on the efficacy of CRC screening for these high risk groups. RESULTS: The estimated preclinical incidence rate was 0. 00396 (95% confidence interval [CI], 0.002944-0.004985), which was 21 times that reported from a cancer registry in 1994. The simultaneous estimations of mean sojourn time (the average duration between the preclinical screen-detectable phase and the clinical phase) and sensitivity were 2.8 years (95% CI, 2.15-4.30) and 95.0% (95% CI, 24.4-99.9%), respectively. Predictions of mortality reduction for people who received annual, biennial, and triennial screening regimes compared with controls were 26% (95% CI, 0-50%), 23% (95% CI, 0-48%), and 21% (95% CI, 0-47%), respectively. CONCLUSIONS: The efficacy of selective colorectal carcinoma screening has been demonstrated in this study. A high preclinical CRC incidence rate also suggests that such a screening strategy might be cost-effective for countries with intermediate or low incidence of CRC. Methods proposed in this study can be used to evaluate the efficacy of CRC screening in similar screening trials.

The natural history of breast carcinoma: what have we learned from screening?

BACKGROUND: The availability of breast carcinoma data from trials of mammographic screening provides an opportunity to study the natural history of breast carcinoma. METHODS: The Swedish Two-County study is a randomized, controlled trial of mammographic screening for breast carcinoma in which 77,080 women were randomized to receive an invitation to mammographic screening and 55,985 were randomized to receive no invitation. During the trial, a total of 2468 breast carcinoma cases were diagnosed. The authors examined the effect of screening on the pathologic attributes of the tumors diagnosed, mortality and survival from breast carcinoma, and the consequences of arresting tumor development by screening. RESULTS: Screening reduces mortality from breast carcinoma largely through its effect in detecting tumors at a smaller size, decreasing the probability of lymph node metastases, and reducing the opportunity for worsening of the grade of malignancy of the tumor. CONCLUSIONS: Breast carcinoma is not a systemic disease at its inception, but is a progressive disease and its development can be arrested by screening. The point at which the tumor's progression is arrested is crucial. Detection of small (<15 mm) and lymph node negative invasive tumors will save lives and confer an opportunity for less radical treatment. Tumor progression in the preclinical phase occurs more rapidly in women age <50 years, suggesting the need for a shorter screening interval for this group.

A randomized controlled trial of day hospital and day centre therapy.

OBJECTIVE: To compare the outcome of day hospital to day centre rehabilitation. DESIGN: Single blind randomized controlled trial with home assessments at baseline (twice), six weeks and three months. SETTING: Mainly rural health district. Day hospital and social services day centres in market towns. SUBJECTS: One hundred and five physically disabled older patients living at home referred for day hospital rehabilitation or maintenance before discharge from hospital (66) or referred as outpatients (39). INTERVENTIONS: Day hospital treatment or day centre rehabilitation by a physiotherapist and two health support workers. MAIN OUTCOME MEASURES: Barthel Index, Philadelphia Geriatric Morale Scale and Caregiver Strain Index. RESULTS: More day centre (23/55) than day hospital patients (6/50) (p <0.001) withdrew from allocated treatment by choice or because of operational difficulties. Both groups improved significantly in functional ability and reduction of care-giver strain by three months but there was no significant difference between groups. The mean improvement in Barthel Index (standard error) for day hospital = +1.5 (0.41) (n = 34) and day centres = +1.5 (0.48) (n = 38). The mean difference (95% confidence interval) between day hospital and day centre was 0 (-1.28, +1.28). Likewise the mean Philadelphia Geriatric Morale Scale improvement for day hospital +1.8 (0.66) (n = 35) and day centres was +0.9 (0.63) (n = 38). The mean difference was -0.88 (-2.7, +0.95). The mean reduction in Caregiver Strain for day hospital was -1.45 (0.5) (n = 23) and day centre was -1.59 (0.47) (n = 27). The difference was -0.14 (1.52, +1.24). (These analyses are all on an intention-to-treat basis.) CONCLUSION: Whilst the improvement in functional ability and care-giver strain was similar in both groups, day centre rehabilitation was less popular and had practical difficulties. If these difficulties can be overcome the model should be tested elsewhere.

Incidence among men of asymptomatic abdominal aortic aneurysms: estimates from 500 screen detected cases.

OBJECTIVES: To determine the incidence of asymptomatic abdominal aortic aneurysms and the implications for an ultrasound screening programme in England and Wales. METHODS: First screen data were obtained from the Chichester and Huntingdon screening studies and used to estimate the prevalence of abdominal aortic aneurysms. The incidence of new, asymptomatic aneurysms was estimated from the prevalence rates observed in the Huntingdon screening study. SETTING: Screening programmes in Huntingdon and Chichester using ultrasound to screen all men over the age of 50 and men over age 65 respectively. RESULTS: The prevalence of abdominal aortic aneurysms ranged between 5.32% and 8.02% and between 6.18% and 9.88% of men aged between 65 and 79 in Chichester and Huntingdon respectively. Annual incidence rates, estimated by age, rose steadily reaching a peak of 0.67% of the Huntingdon population per year at age 65. Thereafter incidence falls. Estimates of the incidence of new asymptomatic abdominal aortic aneurysms, based on the observed prevalence data, were calculated and showed a peak at age 65. CONCLUSIONS: Hypotheses are offered to explain this unexpected early peak in incidence. This information should allow the definition of the optimum age for screening, and the relative benefits of screening at different intervals if widespread screening is adopted in the future.

Evaluation of screening for nasopharyngeal carcinoma: trial design using Markov chain models.

In this paper, we develop a Markov chain model to estimate parameters pertaining to the natural history of nasopharyngeal carcinoma (NPC). The model is of progression from no disease to Epstein-Barr virus (EBV) infection, preclinical screen-detectable tumour and clinical tumour. We derive tentative estimates of the parameters of the model, based on limited published data, to assess the efficacy of serum screening in conjunction with clinical assessment (indirect mirror examination for NPC), for example the average duration of the preclinical screen-detectable phase is estimated as 3.1 years. We further apply these parameters to a hypothetical screening trial in the Hong Kong population to assess the efficacy of serum screening with clinical assessment by different combinations of screening regime. Results suggest: (1) there is no substantial difference between 3-yearly and 6-yearly serum screening; and (2) within the same serum screening regime annual and 3-yearly clinical assessment can prevent 33% and 28% of deaths from NPC respectively. Prediction of deaths and surrogate end points can be used to estimate the required sample size and duration for designing a randomized trial of screening for NPC. Based on these findings and power projections, we suggest a design for a randomized trial in a high incidence area such as Hong Kong.

Markov chain models and estimation of absolute progression rates: application to cataract progression in diabetic adults.

BACKGROUND: We present a case study in the use of Markov chain models of disease progression, with exponential regression to model the effects of covariates. METHODS: An exponential regression model was developed for a three-state Markov chain to model progression of cataracts in diabetic patients, with a view to estimation of absolute progression rates. Two methods of estimation were applied, a non-linear least squares approximation, and Markov Chain Monte Carlo (MCMC). RESULTS: Both methods gave estimated transition rates which can readily be transformed to absolute progression probabilities. Agreement was reasonable for most but not all of the parameters. CONCLUSIONS: The MCMC estimates had more conservative variance estimates.

[Detection of cancer, sensitivity of the test and sensitivity of the screening program]. / Dépistage des cancers, sensibilité du test et sensibilité du programme de dépistage.

In assessment of screening for cancer, no distinction is usually made between the sensitivity of the screening test (St) and the sensitivity of the screening program (Sp). This paper was aimed to distinguish meaning, method for assessment and interest for each of them, and to determine their relationship. Sensitivity of the screening program can be directly assessed with data from on-going trials whilst assessment of sensitivity of screening test requires modelisation techniques, especially for assessing the mean duration of the preclinical phase of cancer. Assuming an exponential distribution of this duration, lambda as the time parameter, a mathematical relation between St and Sp is suggested as follows: [formula: see text] with r being the interval between two screening tests. The implementation of this equation with data from a mass-screening program for colorectal cancer in the department of Calvados allowed us to investigate the influence of the mean preclinical phase and the interval between two screening tests on the value of the sensitivity of the screening procedure. Such a modelisation could be useful in the development of a rational screening policy.