Objective To evaluate the associations between maternal diabetes diagnosed before or during pregnancy and early onset cardiovascular disease (CVD) in offspring during their first four decades of life. Design Population based cohort study. Setting Danish national health registries. Participants All 2 432 000 liveborn children without congenital heart disease in Denmark during 1977-2016. Follow-up began at birth and continued until first time diagnosis of CVD, death, emigration, or 31 December 2016, whichever came first. Exposures for observational studies Pregestational diabetes, including type 1 diabetes (n=22 055) and type 2 diabetes (n=6537), and gestational diabetes (n=26 272). Main outcome measures The primary outcome was early onset CVD (excluding congenital heart diseases) defined by hospital diagnosis. Associations between maternal diabetes and risks of early onset CVD in offspring were studied. Cox regression was used to assess whether a maternal history of CVD or maternal diabetic complications affected these associations. Adjustments were made for calendar year, sex, singleton status, maternal factors (parity, age, smoking, education, cohabitation, residence at childbirth, history of CVD before childbirth), and paternal history of CVD before childbirth. The cumulative incidence was averaged across all individuals, and factors were adjusted while treating deaths from causes other than CVD as competing events. Results During up to 40 years of follow-up, 1153 offspring of mothers with diabetes and 91 311 offspring of mothers who did not have diabetes were diagnosed with CVD. Offspring of mothers with diabetes had a 29% increased overall rate of early onset CVD (hazard ratio 1.29 (95% confidence interval 1.21 to 1.37); cumulative incidence among offspring unexposed to maternal diabetes at 40 years of age 13.07% (12.92% to 13.21%), difference in cumulative incidence between exposed and unexposed offspring 4.72% (2.37% to 7.06%)). The sibship design yielded results similar to those of the unpaired design based on the whole cohort. Both pregestational diabetes (1.34 (1.25 to 1.43)) and gestational diabetes (1.19 (1.07 to 1.32)) were associated with increased rates of CVD in offspring. We also observed varied increased rates of specific early onset CVDs, particularly heart failure (1.45 (0.89 to 2.35)), hypertensive disease (1.78 (1.50 to 2.11)), deep vein thrombosis (1.82 (1.38 to 2.41)), and pulmonary embolism (1.91 (1.31 to 2.80)). Increased rates of CVD were seen in different age groups from childhood to early adulthood until age 40 years. The increased rates were more pronounced among offspring of mothers with diabetic complications (1.60 (1.25 to 2.05)). A higher incidence of early onset CVD in offspring of mothers with diabetes and comorbid CVD (1.73 (1.36 to 2.20)) was associated with the added influence of comorbid CVD but not due to the interaction between diabetes and CVD on the multiplicative scale (P value for interaction 0.94). Conclusions Children of mothers with diabetes, especially those mothers with a history of CVD or diabetic complications, have increased rates of early onset CVD from childhood to early adulthood. If maternal diabetes does have a causal association with increased CVD rate in offspring, the prevention, screening, and treatment of diabetes in women of childbearing age could help to reduce the risk of CVD in the next generation.

Objective To examine the association of maternal hypertensive disorder of pregnancy (HDP) with overall and cause specific mortality in offspring from birth to young adulthood. Design Nationwide population based cohort study. Setting Danish national health registers. Participants All 2 437 718 individuals live born in Denmark, 1978-2018, with follow-up from date of birth until date of death, emigration, or 31 December 2018, whichever came first. Main outcome measures The primary outcome was all cause mortality. Secondary outcomes were 13 specific causes of death in offspring from birth to young adulthood (age 41 years). Cox regression was used to assess the association, taking into consideration several potential confounders. The role of timing of onset and severity of pre-eclampsia, maternal history of diabetes, and maternal education were also studied. Results 102 095 mothers had HDP: 67 683 with pre-eclampsia, 679 with eclampsia, and 33 733 with hypertension. During follow-up to 41 years (median 19.4 (interquartile range 9.7-28.7) years), deaths occurred in 781 (58.94 per 100 000 person years) offspring born to mothers with pre-eclampsia, 17 (133.73 per 100 000 person years) born to mothers with eclampsia, 223 (44.38 per 100 000 person years) born to mothers with hypertension, and 19 119 (41.99 per 100 000 person years) born to mothers with no HDP. The difference in cumulative incidence in overall mortality between cohorts exposed and unexposed to maternal HDP was 0.37% (95% confidence interval 0.11% to 0.64%), and the population attributable fraction for maternal HDP was estimated as 1.09% (95% confidence interval 0.77% to 1.41%). Maternal HDP was associated with a 26% (hazard ratio 1.26, 95% confidence interval 1.18 to 1.34) higher risk of all cause mortality in offspring. The corresponding estimates for maternal pre-eclampsia, eclampsia, and hypertension were 1.29 (1.20 to 1.38), 2.88 (1.79 to 4.63), and 1.12 (0.98 to 1.28). Increased risks were also observed for several cause specific mortalities, such as deaths from conditions originating in the perinatal period (2.04, 1.81 to 2.30), cardiovascular diseases (1.52, 1.08 to 2.13), digestive system diseases (2.09, 1.27 to 3.43), and endocrine, nutritional, and metabolic diseases (1.56, 1.08 to 2.27). The increased risks were more pronounced among offspring of mothers with early onset and severe pre-eclampsia (6.06, 5.35 to 6.86) or with both HDP and diabetes history (1.57, 1.16 to 2.14) or HDP and low education level (1.49, 1.34 to 1.66). Conclusion Maternal HDP, particularly eclampsia and severe pre-eclampsia, is associated with increased risks of overall mortality and various cause specific mortalities in offspring from birth to young adulthood.

Background: Generalized Additive Model (GAM) provides a flexible and effective technique for modelling nonlinear time-series in studies of the health effects of environmental factors. However, GAM assumes that errors are mutually independent, while time series can be correlated in adjacent time points. Here, a GAM with Autoregressive terms (GAMAR) is introduced to fill this gap.Methods: Parameters in GAMAR are estimated by maximum partial likelihood using modified Newton’s method, and the difference between GAM and GAMAR is demonstrated using two simulation studies and a real data example. GAMM is also compared to GAMAR in simulation study 1.Results: In the simulation studies, the bias of the mean estimates from GAM and GAMAR are similar but GAMAR has better coverage and smaller relative error. While the results from GAMM are similar to GAMAR, the estimation procedure of GAMM is much slower than GAMAR. In the case study, the Pearson residuals from the GAM are correlated, while those from GAMAR are quite close to white noise. In addition, the estimates of the temperature effects are different between GAM and GAMAR.Conclusions: GAMAR incorporates both explanatory variables and AR terms so it can quantify the nonlinear impact of environmental factors on health outcome as well as the serial correlation between the observations. It can be a useful tool in environmental epidemiological studies.

Aging is a major risk factor for type 2 diabetes (T2D), but individuals of the same chronological age may vary in their biological aging rate. The associations of Phenotypic Age Acceleration (PhenoAgeAccel), a new accelerated biological aging indicator based on clinical chemistry biomarkers, with the risk of dynamic progression remain unclear. We aimed to assess these associations and examine whether these associations varied by genetic risk and lifestyle. We conducted a prospective cohort study that included 376,083 adults free of T2D and diabetes-related events at baseline in UK Biobank. PhenoAgeAccel > 0 and ≤ 0 were defined as biologically older and younger than chronological age. The outcomes of interest were incident T2D, diabetic complications, and mortality. Hazard ratios (HRs) with 95% confidence intervals (CIs) and population attributable fractions (PAFs) for these associations were calculated using multi-state model. During a median follow-up of 13.7 years, 17,615 participants developed T2D, of whom, 4,524 subsequently developed complications, and 28,373 died. Being biologically older was associated with increased risks of transitions from baseline to T2D (HR 1.77, 95% CI 1.71–1.82; PAF 24.8 [95% CI 23.5–26.2]), from T2D to diabetic complications (1.10, 1.04–1.17; 4.4 [1.4–7.4]), from baseline to all-cause death (1.53, 1.49–1.57; 17.6 [16.6–18.6]), from T2D to all-cause death (1.14, 1.03–1.26; 7.4 [1.8–13.0]), and from diabetic complications to all-cause death (1.32, 1.15–1.51; 15.4 [7.5–23.2]) than being biologically younger. Additionally, participants with older biological age and high genetic risk had a higher risk of incident T2D (4.76,4.43–5.12;18.2 [17.5–19.0]) than those with younger biological age and low genetic risk. Compared with participants with younger biological age and healthy lifestyle, those with older biological age and unhealthy lifestyle had higher risks of transitions in the T2D trajectory, with HRs and PAFs ranging from 1.34 (1.16–1.55; 3.7 [1.8–5.6]) to 5.39 (5.01–5.79; 13.0 [12.4–13.6]). PhenoAgeAccel was consistently associated with an increased risk of all transitions in T2D progression. It has the potential to be combined with genetic risk to identify early T2D incidence risk and may guide interventions throughout T2D progression while tracking their effectiveness.

Purpose: Previous studies have suggested a link between cardiovascular disease (CVD) and the subsequent development of lung cancer. However, empirical evidence on the association of CVDs, particularly type-specific CVDs, with lung cancer incidence and survival remains limited.Methods: The cohort study included 306,285 patients with CVD and 1,222,140 individuals without CVD. We performed stratified Cox regression to estimate the hazard ratio (HR).Results: During up to 42 years of follow-up, 243 (0.08%) and 537 (0.04%) participants were diagnosed with lung cancer among CVD patients and matched individuals, respectively. Patients with CVD had a 67% increased risk of lung cancer (HR: 1.67, 95% confidence interval [CI]: 1.42–1.96). The increased risks were observed in patients with heart disease (1.93, 1.30–2.85), vascular disease (1.88, 1.35–2.61), and hypertensive disease (1.46, 1.15–1.85), respectively. Patients with CVD had a 95% increased risk of lung cancer mortality (1.95, 1.50–2.55), particularly vascular disease (3.24, 1.74–6.02) and heart disease (2.29, 1.23–4.26). Patients with CVD diagnosed in middle adulthood (>40 years old) tended to have a higher incidence risk (3.44, 2.28–5.19) and mortality (3.67, 1.80–7.46) than those diagnosed at younger ages.Conclusions: Our findings on the association of CVD diagnosis, especially heart and vascular disease, with increased risk of lung cancer incidence and mortality suggest that CVD contributes to the development and worsening of lung cancer survival. In particular, people with CVD diagnosed in middle adulthood (>40 years old) would benefit from early preventive evaluation and screening for lung cancer.

Type 2 diabetes mellitus (T2DM) has been suggested to increase the risk of cancers. The aim of this study was to investigate the risk of common cancers in Chinese patients with T2DM. A population-based retrospective cohort study including 36,379 T2DM patients was conducted in Minhang District of Shanghai, China, during 2004 to 2010. All T2DM patients were enrolled from the standardized management system based on local electronic information system. Newly-diagnosed cancer cases were identified by record-linkage with the Shanghai Cancer Registry. Standardized incidence ratios (SIR) and 95 % confidence interval (CI) were used to estimate the risk of cancers among T2DM patients. Overall crude incidence rate (CIR) of cancers was 955.21 per 105 person-years in men and 829.57 per 105 person-years in women. Increased risk of cancer was found in both gender, with an SIR being 1.28 (95 % CI = 1.17–1.38) in men and 1.44 (95 % CI =1.32–1.55) in women. Increased risk of colon (SIR = 1.97; 95 % CI = 1.49 to 2.46), rectum (1.72; 1.23 to 2.21), prostate (2.87; 2.19 to 3.56), and bladder cancers (1.98, 1.28 to 2.68) were observed in men and elevated risk of colon (1.67; 1.25 to 2.08), breast (1.66; 1.38 to 1.95), and corpus uteri cancers (2.87; 2.03 to 3.71) were observed in women. Our results indicate that Chinese patients with T2DM may have an increased risk of some cancers, and the increase may vary by sub-sites of cancers.