Hung-Lin Chen

Tumour development, histology and grade of breast cancers: Prognosis and progression

Using 1,973 breast tumours from women aged 40–69 participating in the Swedish two‐county trial of mammographic screening for breast cancer, we examined the effect of histological type on prognosis and sojourn time (the duration of the preclinical screen‐detectable phase) by age. The hypothesis of dedifferentiation, according to which a cancer of mixed malignancy grade drifts towards grade 3 as the more poorly differentiated part of the tumour grows faster than the well‐differentiated part, was also assessed. Ductal carcinoma in situ, invasive ductal carcinoma of grade 1, mucinous carcinoma and tubular carcinoma were all associated with good survival. Ductal carcinoma of grade 3 was associated with poor survival. Ductal carcinoma of grade 2, lobular and medullary carcinoma were associated with intermediate survival. These patterns were much the same in women aged 40–49 as in women aged 50–69. In women aged 40–49, sojourn time was estimated at about 2 years regardless of histological type. For women aged 50–69, there was a marked association of sojourn time with histological type, the shortest sojourn time being observed for lobular (2 years) and medullary (1.2 years) carcinoma, and the longest for ductal carcinoma grade 1 (7.7 years) and tubular carcinoma (7.1 years). There was strong evidence of a potential to dedifferentiation. A mover‐stayer mixture of Markov chain models estimated that, in women aged 40–54, 91% of ductal tumours have the potential to dedifferentiate and, in women aged 55–69, 38% of ductal tumours have such a potential.

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.

Risk of hospitalization and healthcare cost associated with Diabetes Complication Severity Index in Taiwan's National Health Insurance Research Database ,

OBJECTIVE The aim of this study is to test the validity of adapted Diabetes Complication Severity Index (aDCSI) in predicting the risk of hospitalization and healthcare cost in type 2 diabetic patients using a nationally-representative claims database. STUDY DESIGN Retrospective cohort study used 4years of claims data from Taiwans National Health Insurance Research Database (NHIRD). METHODS Type 2 diabetic patients who had 4-years of enrollment were identified as study subjects (N=136,372). The aDCSI score (sum of diabetic complication with severity levels, range 0-13) and complication count (sum of diabetic complications, range 0-7) were generated using diagnostic codes for each patient. Poisson model and linear regression model were conducted to predict risk of hospitalization and healthcare costs associated with aDCSI score and count of diabetic complications. RESULTS The aDCSI score (risk ratio 1.51 to 10.32 categorically, and 1.41 linearly) and count of diabetic complications (risk ratio 1.56 to 12.20 categorically, and 1.66 linearly) were significantly positively associated with risk of hospitalization. A one-point increase in the aDCSI score was positively associated with increased healthcare costs. CONCLUSIONS The performance of aDCSI in predicting risk of hospitalization and healthcare cost in the nationally-representative claims database is similar to those reported in the original study. It may serve as an efficient tool for stratifying type 2 diabetic patients for disease management programs and population-based studies.

Evaluation by Markov chain models of a non-randomised breast cancer screening programme in women aged under 50 years in Sweden.

STUDY OBJECTIVE: To apply Markov chain models that have previously been used on data in randomised trials of breast cancer screening to data from an uncontrolled service screening programme; to compare results with those from a randomised trial. DESIGN: A service screening programme in Uppsala county, Sweden, inviting 25,660 women aged 39-49 to mammographic screening every 20 months, and the Swedish Two-County Trial inviting 19,844 women aged 40-49 to two yearly screening, compared with 15,604 women of the same age in an unscreened control group. Data were analysed using Markov chain models and quasi-likelihood estimation procedures. MAIN RESULTS: The results with respect to parameters of disease progression were very similar between the two studies. Use of estimated progression rates to predict the effect on mortality ranged from a 10% to a 17% reduction in breast cancer mortality in the Two-County Study and predicted a 15% reduction in the Uppsala programme. These compare well with the observed mortality reduction of 13% in the Two-County Trial. CONCLUSIONS: The screening in the Uppsala programme is likely to have a similar effect to that observed in the Two-County Trial. It is feasible to evaluate non-randomised service screening programmes using Markov chain models.

Somatic neuropathy is an independent predictor of all- and diabetes-related mortality in type 2 diabetic patients: A population-based 5-year follow-up study (KCIS No. 29)

Background and purpose:  To investigate the relationships of diabetic neuropathy to all‐cause and diabetes‐related mortality in patients with type 2 diabetes after controlling for significant correlates.

Domperidone, cytochrome P450 3A4 isoenzyme inhibitors and ventricular arrhythmia: a nationwide case-crossover study.

Recent evidence suggested that oral form of domperidone may possess pro‐arrhythmic effects and increase the risk of ventricular arrhythmia. The concomitant use of cytochrome P450 (CYP) 3A4 isoenzyme inhibitors may further potentiate this association. Nevertheless, empirical data supporting these associations are very limited. The aim of this study was to investigate the association between oral domperidone, CYP 3A4 inhibitors, and ventricular arrhythmia.

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

SummaryIn 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.

Estimation of disease progression parameters from case-control data: application to mammographic patterns and breast cancer natural history.

BACKGROUND Estimations of mean sojourn time (MST) and sensitivity (S) in disease screening have been previously calculated from case-control data, using simple models which did not include covariates. Many studies have shown an effect of mammographic parenchymal pattern (MPP) on breast-cancer risk and tumour histology. We have expanded previous models on these to estimate MST and S with the effects of MPP as a covariate. METHODS Data were from a nested case-control study within the East Anglian screening programme, with 875 cases and 2,601 controls. Estimates of disease progression and screening parameters were based on conditional likelihood calculation, using a Markov process model. Ninety-five per cent confidence intervals (CI) were calculated using the profile likelihood wherever possible and using a numerical estimate of the information matrix or the area under the likelihood curve where necessary. RESULTS We obtained estimates of the incidence of preclinical disease, rate of transition from preclinical to clinical and screening sensitivity, and evaluated the association of these parameters with mammographic parenchymal pattern. A higher incidence of preclinical disease was found for high-risk MPP [relative incidence = 1.62 (95% CI: 0.89; 2.73)]. However, no difference in progression rate from preclinical to clinical disease between different MPP was found. Dense MPPs were associated with decreased sensitivity [relative sensitivity = 0.24 (95% CI: 0.06; 15)]. Wide CIs were found, probably being a consequence of the relative sparsity of interval cancer data. DISCUSSION It is possible to estimate multiple parameters of disease progression and screening quality from case-control data. The reduction in sensitivity of the screening process associated with high-risk patterns presented here, could be of paramount interest for proposing new screening strategies, such as possible additional screening tools.

Analysis of household data on influenza epidemic with Bayesian hierarchical model.

Abstract Data used for modelling the household transmission of infectious diseases, such as influenza, have inherent multilevel structures and correlated property, which make the widely used conventional infectious disease transmission models (including the Greenwood model and the Reed–Frost model) not directly applicable within the context of a household (due to the crowded domestic condition or socioeconomic status of the household). Thus, at the household level, the effects resulting from individual-level factors, such as vaccination, may be confounded or modified in some way. We proposed the Bayesian hierarchical random-effects (random intercepts and random slopes) model under the context of generalised linear model to capture heterogeneity and variation on the individual, generation, and household levels. It was applied to empirical surveillance data on the influenza epidemic in Taiwan. The parameters of interest were estimated by using the Markov chain Monte Carlo method in conjunction with the Bayesian directed acyclic graphical models. Comparisons between models were made using the deviance information criterion. Based on the result of the random-slope Bayesian hierarchical method under the context of the Reed–Frost transmission model, the regression coefficient regarding the protective effect of vaccination varied statistically significantly from household to household. The result of such a heterogeneity was robust to the use of different prior distributions (including non-informative, sceptical, and enthusiastic ones). By integrating out the uncertainty of the parameters of the posterior distribution, the predictive distribution was computed to forecast the number of influenza cases allowing for random-household effect.

Cumulative Burden of Glucocorticoid-related Adverse Events in Patients with Systemic Lupus Erythematosus: Findings from a 12-year Longitudinal Study

Objective. The aim of this population-based study is to examine the adverse events (AE) associated with longitudinal systemic glucocorticoid (GC) use among an ethnic Chinese systemic lupus erythematosus (SLE) cohort. Methods. Our study subjects were patients with newly diagnosed SLE aged 18 and older who received at least 1 prescription of systemic GC between 2001 and 2012 from Taiwan’s National Health Insurance Research Database (NHIRD). The earliest prescription date of systemic GC for each subject was defined as the index date. For each subject, we calculated the average prednisolone-equivalent dose and the medication possession ratio (MPR) of GC use every 90 days for each patient after the index date. Patients with a diagnosis of AE (defined by the International Classification of Diseases-9-Clinical Modification diagnosis code) during the followup were also identified from the NHIRD. Generalized estimating equations adjusted for propensity score were applied to examine the association between longitudinal GC use and risks of prespecified AE (musculoskeletal, gastrointestinal, ophthalmologic, infectious, cardiovascular, neuropsychiatric, metabolic, and dermatologic diseases). Results. We identified 11,288 patients with SLE (mean followup: 6.28 yrs). Higher doses and higher MPR of GC were associated with increased risk of osteonecrosis [adjusted OR (aOR) 2.87–9.09]. Similar results were found regarding the risk of osteoporosis (aOR 1.71–3.67), bacterial infection (aOR 2.12–3.89), Cushingoid syndrome (aOR 6.51–62.03), and sleep disorder (aOR 1.42–3.59). Conclusion. To our knowledge, this is the first study to show that the dose and intensity of longitudinal use of GC were both associated with risk of AE among a nationwide Asian SLE cohort.