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To compare the validity and robustness of five methods for handling missing characteristics when using cardiovascular disease risk prediction models for individual patients in a real-world clinical setting. The performance of the missing data methods was assessed using data from the Swedish National Diabetes Registry (n = 419,533) with external validation using the Scottish Care Information ˗ diabetes database (n = 226,953). Five methods for handling missing data were compared. Two methods using submodels for each combination of available data, two imputation methods: conditional imputation and median imputation, and one alternative modeling method, called the naïve approach, based on hazard ratios and populations statistics of known risk factors only. The validity was compared using calibration plots and c-statistics. C-statistics were similar across methods in both development and validation data sets, that is, 0.82 (95% CI 0.82–0.83) in the Swedish National Diabetes Registry and 0.74 (95% CI 0.74–0.75) in Scottish Care Information-diabetes database. Differences were only observed after random introduction of missing data in the most important predictor variable (i.e., age). Validity and robustness of median imputation was not dissimilar to more complex methods for handling missing values, provided that the most important predictor variables, such as age, are not missing.

Comparator arms in randomized clinical trials may be impractical and/or unethical to assemble in rare diseases. In the absence of comparator arms, evidence generated from external control studies has been used to support successful regulatory submissions and health technology assessments (HTA). However, conducting robust and rigorous external control arm studies is challenging and despite all efforts, residual biases may remain. As a result, regulatory and HTA agencies may request additional external control analyses so that decisions may be made based upon a body of supporting evidence.This paper introduces external control studies and provides an overview of the key methodological issues to be considered in the design of these studies. A series of case studies are presented in which evidence derived from one or more external controls was submitted to regulatory and HTA agencies to provide support for the consistency of findings.

Aims/hypothesisThe aim of this study was to examine how BMI influences the association between Asian ethnicity and risk of gestational diabetes (GDM).MethodsThis population-based cohort study included pregnant women without pre-existing diabetes mellitus in Ontario, Canada between 2012 and 2014. Women of Chinese and South Asian ethnicity were identified using a validated surname algorithm. GDM was ascertained using hospitalisation codes. The relationship between ethnicity and GDM was modelled using modified Poisson regression, adjusted for maternal age, pre-pregnancy BMI, parity, previous GDM, long-term residency status, income quintile and smoking status. An interaction term between ethnicity and pre-pregnancy BMI was tested.ResultsOf 231,618 pregnant women, 9289 (4.0%) were of South Asian ethnicity and 12,240 (5.3%) were of Chinese ethnicity. Relative to women from the general population, in whom prevalence of GDM was 4.3%, the adjusted RR of GDM was higher among those of South Asian ethnicity (1.81 [95% CI 1.64, 1.99]) and Chinese ethnicity (1.66 [95% CI 1.53, 1.80]). The association between GDM and Asian ethnicity remained significant across BMI categories but differed according to BMI. The prevalence of GDM exceeded 5% at an estimated BMI of 21.5 kg/m2 among South Asian women, 23.0 kg/m2 among Chinese women and 29.5 kg/m2 among the general population.Conclusions/interpretationThe risk of GDM is significantly higher in South Asian and Chinese women, whose BMI is lower than that of women in the general population. Accordingly, targeted GDM prevention strategies may need to consider lower BMI cut-points for Asian populations.

Aims/hypothesis An excess cancer incidence of 20–25% has been identified among persons with diabetes, most of whom have type 2 diabetes. We aimed to describe the association between type 1 diabetes and cancer incidence. Methods Persons with type 1 diabetes were identified from five nationwide diabetes registers: Australia (2000–2008), Denmark (1995–2014), Finland (1972–2012), Scotland (1995–2012) and Sweden (1987–2012). Linkage to national cancer registries provided the numbers of incident cancers in people with type 1 diabetes and in the general population. We used Poisson models with adjustment for age and date of follow up to estimate hazard ratios for total and site-specific cancers. Results A total of 9,149 cancers occurred among persons with type 1 diabetes in 3.9 million person-years. The median age at cancer diagnosis was 51.1 years (interquartile range 43.5–59.5). The hazard ratios (HRs) (95% CIs) associated with type 1 diabetes for all cancers combined were 1.01 (0.98, 1.04) among men and 1.07 (1.04, 1.10) among women. HRs were increased for cancer of the stomach (men, HR 1.23 [1.04, 1.46]; women, HR 1.78 [1.49, 2.13]), liver (men, HR 2.00 [1.67, 2.40]; women, HR 1.55 [1.14, 2.10]), pancreas (men, HR 1.53 [1.30, 1.79]; women, HR 1.25 [1.02,1.53]), endometrium (HR 1.42 [1.27, 1.58]) and kidney (men, HR 1.30 [1.12, 1.49]; women, HR 1.47 [1.23, 1.77]). Reduced HRs were found for cancer of the prostate (HR 0.56 [0.51, 0.61]) and breast (HR 0.90 [0.85, 0.94]). HRs declined with increasing diabetes duration. Conclusion Type 1 diabetes was associated with differences in the risk of several common cancers; the strength of these associations varied with the duration of diabetes.

Aims/hypothesisMortality has declined in people with type 1 diabetes in recent decades. We examined how the pattern of decline differs by country, age and sex, and how mortality trends in type 1 diabetes relate to trends in general population mortality.MethodsWe assembled aggregate data on all-cause mortality during the period 2000–2016 in people with type 1 diabetes aged 0–79 years from Australia, Denmark, Latvia, Scotland, Spain (Catalonia) and the USA (Kaiser Permanente Northwest). Data were obtained from administrative sources, health insurance records and registries. All-cause mortality rates in people with type 1 diabetes, and standardised mortality ratios (SMRs) comparing type 1 diabetes with the non-diabetic population, were modelled using Poisson regression, with age and calendar time as quantitative variables, describing the effects using restricted cubic splines with six knots for age and calendar time. Mortality rates were standardised to the age distribution of the aggregate population with type 1 diabetes.ResultsAll six data sources showed a decline in age- and sex-standardised all-cause mortality rates in people with type 1 diabetes from 2000 to 2016 (or a subset thereof), with annual changes in mortality rates ranging from −2.1% (95% CI −2.8%, −1.3%) to −5.8% (95% CI −6.5%, −5.1%). All-cause mortality was higher for male individuals and for older individuals, but the rate of decline in mortality was generally unaffected by sex or age. SMR was higher in female individuals than male individuals, and appeared to peak at ages 40–70 years. SMR declined over time in Denmark, Scotland and Spain, while remaining stable in the other three data sources.Conclusions/interpretationAll-cause mortality in people with type 1 diabetes has declined in recent years in most included populations, but improvements in mortality relative to the non-diabetic population are less consistent.

Purpose To assess real-world treatment patterns in patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) who received cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant at first line. Methods Patient characteristics, treatment history, and outcomes data were extracted from the French ‘Système National des Données de Santé’ (SNDS) database for patients diagnosed with HR+/HER2- mBC between January 2014 and June 2019 and who received combination therapy with a CDK4/6 inhibitor and endocrine therapy. Kaplan-Meier methodology was used to assess time to next treatment (TTNT) and time to treatment discontinuation (TTTD). Results The cohort comprised 6061 patients including 4032 patients who received CDK4/6 inhibitors + AIs and 2029 patients who received CDK4/6 inhibitors + fulvestrant. Median follow-up was 13.5 months (IQR 9.5–18.1). The median TTTD of first line treatment with CDK4/6 inhibitors + AIs and CDK4/6 inhibitors + fulvestrant was 17.3 months (95% CI 16.8–17.9) and 9.7 months (95% CI 9.0–10.2), respectively. Chemotherapy was the most common second line therapy. Median TTTD of subsequent treatment lines was progressively shorter following first line treatment with CDK4/6 inhibitors + AIs (2nd line: 4.6 months (95% CI 4.4–4.9) and with CDK4/6 inhibitors + fulvestrant (2nd line: 4.7 months (95% CI 4.3–5.1). TTNT was longer than TTTD across lines of therapy. Conclusion This real-world analysis confirms the effectiveness of CDK4/6 inhibitor-based regimens in French patients and highlights the frequent use of chemotherapy as second line therapy.

Aims/hypothesisThe aim of the study was to examine trends in the incidence and case fatality of acute myocardial infarction (AMI) and in hospital admissions for angina and coronary revascularisation procedures in people with type 2 diabetes and in people without diabetes in Scotland between 2006 and 2015.MethodsIn this retrospective cohort study, AMI, angina and revascularisation event data were obtained for adults from hospital admissions and death records linked to a population-based diabetes register. Incidence by diabetes status was estimated using negative binomial models with adjustment or stratification by age, sex, deprivation and calendar year. Logistic regression was used to estimate AMI case fatality by diabetes status.ResultsThere were 129,926 incident AMI events, 41,263 angina admissions and 69,875 coronary revascularisation procedures carried out during 34.9 million person-years of follow-up. The adjusted incidence of AMI, angina and revascularisation procedures declined by 2.0% (95% CI 1.73%, 2.26%), 9.62% (95% CI 9.22%, 10.01%) and 0.35% (95% CI −0.09%, 0.79%) per year, respectively. The rate of decline did not differ materially by diabetes status. RRs of AMI for type 2 diabetes were 1.86 (95% CI 1.74, 1.98) for men and 2.32 (95% CI 2.15, 2.51) for women. Of the 77,211 people admitted to hospital with a first AMI, 7842 (10.2%) died within 30 days of admission. Case fatality was higher in people with type 2 diabetes than in people without diabetes and declined in both groups by 7.93% (95% CI 7.03%, 8.82%) per year.Conclusions/interpretationThe incidence of AMI, angina, revascularisation and AMI case fatality has declined over time, but the increased risk associated with type 2 diabetes has remained approximately constant.

Aims/hypothesisWe aimed to report current rates of CVD in type 1 diabetes and to develop a CVD risk prediction tool for type 1 diabetes.MethodsA cohort of 27,527 people with type 1 diabetes without prior CVD was derived from the national register in Scotland. Incident CVD events during 199,552 person-years of follow-up were ascertained using hospital admissions and death registers. A Poisson regression model of CVD was developed and then validated in the Swedish National Diabetes Register (n = 33,183). We compared the percentage with a high 10 year CVD risk (i.e., ≥10%) using the model with the percentage eligible for statins using current guidelines by age.ResultsThe age-standardised rate of CVD per 100,000 person-years was 4070 and 3429 in men and women, respectively, with type 1 diabetes in Scotland, and 4014 and 3956 in men and women in Sweden. The final model was well calibrated (Hosmer–Lemeshow test p > 0.05) and included a further 22 terms over a base model of age, sex and diabetes duration (C statistic 0.82; 95% CI 0.81, 0.83). The model increased the base model C statistic from 0.66 to 0.80, from 0.60 to 0.75 and from 0.62 to 0.68 in those aged <40, 40–59 and ≥ 60 years, respectively (all p values <0.005). The model required minimal calibration in Sweden and had a C statistic of 0.85. Under current guidelines, >90% of those aged 20–39 years and 100% of those ≥40 years with type 1 diabetes were eligible for statins, but it was not until age 65 upwards that 100% had a modelled risk of CVD ≥10% in 10 years.Conclusions/interpretationA prediction tool such as that developed here can provide individualised risk predictions. This 10 year CVD risk prediction tool could facilitate patient discussions regarding appropriate statin prescribing. Apart from 10 year risk, such discussions may also consider longer-term CVD risk, the potential for greater benefits from early vs later statin intervention, the potential impact on quality of life of an early CVD event and evidence on safety, all of which could influence treatment decisions, particularly in younger people with type 1 diabetes.

Aims/hypothesis The relative contribution of increasing incidence and declining mortality to increasing prevalence of type 2 diabetes in Scotland is unclear. Trends in incidence and mortality rates are described for type 2 diabetes in Scotland between 2004 and 2013 by age, sex and socioeconomic deprivation. Methods Data for incident and prevalent cases of type 2 diabetes were obtained from the Scottish national diabetes register with number of deaths identified from linkage to mortality records. Population size and death data for Scotland by age, sex and socioeconomic deprivation were obtained from National Records of Scotland. Age- and sex-specific incidence and mortality rates stratified by year and deciles of socioeconomic status were calculated using Poisson models. Results There were 180,290 incident cases of type 2 diabetes in Scotland between 2004 and 2013. Overall, incidence of type 2 diabetes remained stable over time and was 4.88 (95% CI 4.84, 4.90) and 3.33 (3.28, 3.32) per 1000 in men and women, respectively. However, incidence increased among young men, remained stable in young women, and declined in older men and women. Incidence rates declined in all socioeconomic groups but increased after 2008 in the most deprived groups. Standardised mortality ratios associated with diabetes, adjusted for age and socioeconomic group, were 1.38 (1.36, 1.41) in men and 1.49 (1.45, 1.52) in women, and remained constant over time. Conclusions/interpretation Incidence of type 2 diabetes has stabilised in recent years suggesting that increasing prevalence may be primarily attributed to declining mortality. Prevention of type 2 diabetes remains important, particularly among socioeconomically deprived populations.