Selecting the primary endpoint in a randomized clinical trial: the ARE method

The decision on the primary endpoint in a randomized clinical trial is of paramount importance and the combination of several endpoints might be a reasonable choice. Gómez and Lagakos (2013) have developed a method that quantifies how much more efficient it could be to use a composite instead of an individual relevant endpoint. From the information provided by the frequencies of observing the component endpoints in the control group and by the relative treatment effects on each individual endpoint, the asymptotic relative efficiency (ARE) can be computed. This article presents the applicability of the ARE method as a practical and objective tool to evaluate which components, among the plausible ones, are more efficient in the construction of the primary endpoint. The method is illustrated with two real cardiovascular clinical trials and is extended to allow for different dependence structures between the times to the individual endpoints. The influence of this choice on the recommendation on whether or not to use the composite endpoint as the primary endpoint for the investigation is studied. We conclude that the recommendation between using the composite or the relevant endpoint only depends on the frequencies of the endpoints and the relative effects of the treatment.Peer ReviewedPostprint (author's final draft

Extension of the asymptotic relative efficiency method to select the primary endpoint in a randomized clinical trial

We extend the ARE method proposed in Gómez and Lagakos (2013) devised to decide which primary endpoint to choose when comparing two treatments in a randomized clinical trial. The ARE method is based on the Asymptotic Relative Efficiency (ARE) between two logrank tests to compare two treatments: one is based on a relevant endpoint E1 while the other is based on a composite endpoint E* = E1 ¿ E2, where E2 is an additional endpoint. The ARE depends, besides some intuitive parameters, on the joint law of the times T1 and T2 from randomization to E1 and E2, respectively. Gómez and Lagakos (2013) characterize this joint law by means of Frank’s copula. In our work, several families of copulas can be chosen for the bivariate survival function of (T1, T2) so that different dependence struc- tures between T1 and T2 are feasible. We motivate the problem and show how to apply the method through a real cardiovascular clinical trial. We explore the influence of the copula chosen into the ARE value by means of a simulation study. We conclude that the recommendation on whether or not to use the composite endpoint as the primary endpoint for the investigation is, almost always, independent of the copula chosen.Preprin

Using Gumbel copula to assess the efficiency of the main endpoint in a randomized clinical trial and comparison with Frank copula

In time-to-event randomized clinical trials, it is common to use composite endpoints as the main endpoint when comparing two treatment groups. A new statistical methodology has been recently developed in order to derives guidelines for deciding whether to expand the use a single or composite endpoint. This methodology, developed by Gómez and Lagakos, is based on the asymptotic relative efficiency (ARE) of a logrank test for comparing two treatment groups with respect to a relevant endpoint versus the composite endpoint. In order to compute the ARE, it is necessary to have the joint law of the time to the relevant and additional endpoints and it is obtained using Frank copula. The main aim of this master thesis is to develop this methodology using Gumbel copula and to compare it with the results obtained using Frank copula. This project shows that the results obtained using Gumbel copula are similar to the ones obtained using Frank copula and, therefore, we conclude that the ARE method is robust for the choice of the copula when restricted to Frank and Gumbel copulas.Gómez i Lagakos calculen l'eficiència relativa (ARE) del logrank per comparar dos tractaments A i B usant el temps T1 fins E1 o T* fins E*= E1 U E2. L'ARE s'obté fixant la llei de (T1, T2) i es modela via la còpula de Frank. L'objectiu és modelar la llei amb altres còpulas i estudiar les repercussions que aquest canvi té en el càlcul del ARE. L'estudiant haurà d'estudiar la metodologia de GL; estudiar les propietats de les còpules; escollir una còpula diferent de la de Frank i programar l'ARE; i discutir quan robust és l'ARE en front d'un canvi de còpula

Lifespan variation among people with a given disease or condition

In addition to fundamental mortality metrics such as mortality rates and mortality rate ratios, life expectancy is also commonly used to investigate excess mortality among a group of individuals diagnosed with specific diseases or conditions. However, as an average measure, life expectancy ignores the heterogeneity in lifespan. Interestingly, the variation in lifespan-a measure commonly used in the field of demography-has not been estimated for people with a specific condition. Based on recent advances in methodology in research within epidemiology and demography, we discuss two metrics, namely, the average life disparity and average lifetable entropy after diagnosis, which estimate the variation in lifespan for time-varying conditions in both absolute and relative aspects. These metrics are further decomposed into early and late components, separated by their threshold ages. We use mortality data for women with mental disorders from Danish registers to design a population-based study and measure such metrics. Compared with women from the general population, women with a mental disorder had a shorter average remaining life expectancy after diagnosis (37.6 years vs. 44.9 years). In addition, women with mental disorders also experienced a larger average lifespan variation, illustrated by larger average life disparity (9.5 years vs 9.1 years) and larger average lifetable entropy (0.33 vs 0.27). More specifically, we found that women with a mental disorder had a larger early average life disparity but a smaller late average life disparity. Unlike the average life disparity, both early and late average lifetable entropy were higher for women with mental disorders compared to the general population. In conclusion, the metric proposed in our study complements the current research focusing merely on life expectancy and further provides a new perspective into the assessment of people's health associated with time-varying conditions

Association between metabolic syndrome and 13 types of cancer in Catalonia : A matched case-control study

Metabolic syndrome (MS) is the simultaneous occurrence of a cluster of predefined cardiovascular risk factors. Although individual MS components are associated with increased risk of cancer, it is still unclear whether the association between MS and cancer differs from the association between individual MS components and cancer. The aim of this matched case-control study was to estimate the association of 13 types of cancer with (1) MS and (2) the diagnosis of 0, 1 or 2 individual MS components. Cases included 183,248 patients ≥40 years from the SIDIAP database with incident cancer diagnosed between January 2008-December 2017. Each case was matched to four controls by inclusion date, sex and age. Adjusted conditional logistic regression models were used to evaluate the association between MS and cancer risk, comparing the effect of global MS versus having one or two individual components of MS. MS was associated with an increased risk of the following cancers: colorectal (OR: 1.28, 95%CI: 1.23-1.32), liver (OR: 1.93, 95%CI: 1.74-2.14), pancreas (OR: 1.79, 95%CI: 1.63-1.98), post-menopausal breast (OR: 1.10, 95%CI: 1.06-1.15), pre-menopausal endometrial (OR: 2.14, 95%CI: 1.74-2.65), post-menopausal endometrial (OR: 2.46, 95%CI: 2.20-2.74), bladder (OR: 1.41, 95%CI: 1.34-1.48), kidney (OR: 1.84, 95%CI: 1.69-2.00), non-Hodgkin lymphoma (OR: 1.23, 95%CI: 1.10-1.38), leukaemia (OR: 1.42, 95%CI: 1.31-1.54), lung (OR: 1.11, 95%CI: 1.05-1.16) and thyroid (OR: 1.71, 95%CI: 1.50-1.95). Except for prostate, pre-menopause breast cancer and Hodgkin and non-Hodgkin lymphoma, MS is associated with a higher risk of cancer than 1 or 2 individual MS components. Estimates were significantly higher in men than in women for colorectal and lung cancer, and in smokers than in non-smokers for lung cancer. MS is associated with a higher risk of developing 11 types of common cancer, with a positive correlation between number of MS components and risk of cancer

Impact of Glucose-Lowering Agents on the Risk of Cancer in Type 2 Diabetic Patients. The Barcelona Case-Control Study

The aim of the present study is to evaluate the impact of glucose-lowering agents in the risk of cancer in a large type 2 diabetic population. A nested case-control study was conducted within a defined cohort (275,164 type 2 diabetic patients attending 16 Primary Health Care Centers of Barcelona). Cases (n = 1,040) comprised those subjects with any cancer diagnosed between 2008 and 2010, registered at the Cancer Registry of Hospital Vall d'Hebron (Barcelona). Three control subjects for each case (n = 3,120) were matched by age, sex, diabetes duration, and geographical area. The treatments analyzed (within 3 years prior to cancer diagnosis) were: insulin glargine, insulin detemir, human insulin, fast-acting insulin and analogues, metformin, sulfonylureas, repaglinide, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and alpha glucosidase inhibitors. Conditional logistic regressions were used to calculate the risk of cancer associated with the use of each drug adjusted by age, BMI, dose and duration of treatment, alcohol use, smoking habit, and diabetes duration. No differences were observed between case and control subjects for the proportion, dose or duration of exposure to each treatment. None of the types of insulin and oral agents analyzed showed a significant increase in the risk of cancer. Moreover, no cancer risk was observed when glargine was used alone or in combination with metformin. Our results suggest that diabetes treatment does not influence the risk of cancer associated with type 2 diabetes. Therefore, an eventual increase of cancer should not be a reason for biasing the selection of any glucose-lowering treatment in type 2 diabetic population

Educational attainment and mortality in schizophrenia

Background Individuals suffering from schizophrenia have a reduced life expectancy with cardiovascular disease (CVD) as a major contributor. Low educational attainment is associated with schizophrenia, as well as with all-cause and CVD mortality. However, it is unknown to what extent low educational attainment can explain the increased mortality in individuals with schizophrenia. Aim Here, we quantify associations between educational attainment and all-cause and CVD mortality in individuals with schizophrenia, and compare them with the corresponding associations in the general population. Method All Norwegian citizens born between January 1, 1925, and December 31, 1959, were followed up from January 1, 1990, to December 31, 2014. The total sample included 1,852,113 individuals, of which 6548 were registered with schizophrenia. We estimated hazard ratios (HR) for all-cause and CVD mortality with Cox models, in addition to life years lost. Educational attainment for index persons and their parents were included in the models. Results In the general population individuals with low educational attainment had higher risk of all-cause (HR: 1.48 [95% CI: 1.47–1.49]) and CVD (HR: 1.59 [95% CI: 1.57–1.61]) mortality. In individuals with schizophrenia these estimates were substantially lower (all-cause: HR: 1.13 [95% CI: 1.05–1.21] and CVD: HR: 1.12 [95% CI: 0.98–1.27]). Low educational attainment accounted for 3.28 (3.21–3.35) life years lost in males and 2.48 (2.42–2.55) years in females in the general population, but was not significantly associated with life years lost in individuals with schizophrenia. Results were similar for parental educational attainment. Conclusions Our results indicate that while individuals with schizophrenia in general have lower educational attainment and higher mortality rates compared with the general population, the association between educational attainment and mortality is smaller in schizophrenia subjects than in the general population.publishedVersio

Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study

Background: The provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results. Methods and findings: In a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality. Conclusions: In this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.publishedVersio

Relationship between efficiency and clinical effectiveness indicators in an adjusted model of resource consumption : a cross-sectional study

Background: Adjusted clinical groups (ACG®) have been widely used to adjust resource distribution; however, the relationship with effectiveness has been questioned. The purpose of the study was to measure the relationship between efficiency assessed by ACG® and a clinical effectiveness indicator in adults attended in Primary Health Care Centres (PHCs). Methods: Research design: cross-sectional study. Subjects: 196, 593 patients aged >14 years in 13 PHCs in Catalonia (Spain). Measures: Age, sex, PHC, basic care team (BCT), visits, episodes (diagnoses), and total direct costs of PHC care and co-morbidity as measured by ACG® indicators: Efficiency indices for costs, visits, and episodes (costs EI, visits EI, episodes EI); a complexity or risk index (RI); and effectiveness measured by a general synthetic index (SI). The relationship between EI, RI, and SI in each PHC and BCT was measured by multiple correlation coefficients (r). Results: In total, 56 of the 106 defined ACG® were present in the study population, with five corresponding to 44.5% of the patients, 11 to 68.0% of patients, and 30 present in less than 0.5% of the sample. The RI in each PHC ranged from 0.9 to 1.1. Costs, visits, and episodes had similar trends for efficiency in six PHCs. There was moderate correlation between costs EI and visits EI (r = 0.59). SI correlation with episodes EI and costs EI was moderate (r = 0.48 and r = −0.34, respectively) and was r = −0.14 for visits EI. Correlation between RI and SI was r = 0.29. Conclusions: The Efficiency and Effectiveness ACG® indicators permit a comparison of primary care processes between PHCs. Acceptable correlation exists between effectiveness and indicators of efficiency in episodes and costs

Life expectancy and disease burden in the Nordic countries : results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017

Background The Nordic countries have commonalities in gender equality, economy, welfare, and health care, but differ in culture and lifestyle, which might create country-wise health differences. This study compared life expectancy, disease burden, and risk factors in the Nordic region. Methods Life expectancy in years and age-standardised rates of overall, cause-specific, and risk factor-specific estimates of disability-adjusted life-years (DALYs) were analysed in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Data were extracted for Denmark, Finland, Iceland, Norway, and Sweden (ie, the Nordic countries), and Greenland, an autonomous area of Denmark. Estimates were compared with global, high-income region, and Nordic regional estimates, including Greenland. Findings All Nordic countries exceeded the global life expectancy; in 2017, the highest life expectancy was in Iceland among females (85.9 years [95% uncertainty interval [UI] 85.5-86.4] vs 75.6 years [75.3-75.9] globally) and Sweden among males (80.8 years [80.2-81.4] vs 70.5 years [70.1-70.8] globally). Females (82.7 years [81.9-83.4]) and males (78.8 years [78.1-79.5]) in Denmark and males in Finland (78.6 years [77.8-79.2]) had lower life expectancy than in the other Nordic countries. The lowest life expectancy in the Nordic region was in Greenland (females 77.2 years [76.2-78.0], males 70.8 years [70.3-71.4]). Overall disease burden was lower in the Nordic countries than globally, with the lowest age-standardised DALY rates among Swedish males (18 555.7 DALYs [95% UI 15 968.6-21 426.8] per 100 000 population vs 35 834.3 DALYs [33 218.2-38 740.7] globally) and Icelandic females (16 074.1 DALYs [13 216.4-19 240.8] vs 29 934.6 DALYs [26 981.9-33 211.2] globally). Greenland had substantially higher DALY rates (26 666.6 DALYs [23 478.4-30 218.8] among females, 33 101.3 DALYs [30 182.3-36 218.6] among males) than the Nordic countries. Country variation was primarily due to differences in causes that largely contributed to DALYs through mortality, such as ischaemic heart disease. These causes dominated male disease burden, whereas non-fatal causes such as low back pain were important for female disease burden. Smoking and metabolic risk factors were high-ranking risk factors across all countries. DALYs attributable to alcohol use and smoking were particularly high among the Danes, as was alcohol use among Finnish males. Interpretation Risk factor differences might drive differences in life expectancy and disease burden that merit attention also in high-income settings such as the Nordic countries. Special attention should be given to the high disease burden in Greenland. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.Peer reviewe