Christopher Patterson

Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study

BACKGROUND The incidence of type 1 diabetes in children younger than 15 years is increasing. Prediction of future incidence of this disease will enable adequate fund allocation for delivery of care to be planned. We aimed to establish 15-year incidence trends for childhood type 1 diabetes in European centres, and thereby predict the future burden of childhood diabetes in Europe. METHODS 20 population-based EURODIAB registers in 17 countries registered 29 311 new cases of type 1 diabetes, diagnosed in children before their 15th birthday during a 15-year period, 1989-2003. Age-specific log linear rates of increase were estimated in five geographical regions, and used in conjunction with published incidence rates and population projections to predict numbers of new cases throughout Europe in 2005, 2010, 2015, and 2020. FINDINGS Ascertainment was better than 90% in most registers. All but two registers showed significant yearly increases in incidence, ranging from 0.6% to 9.3%. The overall annual increase was 3.9% (95% CI 3.6-4.2), and the increases in the age groups 0-4 years, 5-9 years, and 10-14 years were 5.4% (4.8-6.1), 4.3% (3.8-4.8), and 2.9% (2.5-3.3), respectively. The number of new cases in Europe in 2005 is estimated as 15 000, divided between the 0-4 year, 5-9 year, and 10-14 year age-groups in the ratio 24%, 35%, and 41%, respectively. In 2020, the predicted number of new cases is 24 400, with a doubling in numbers in children younger than 5 years and a more even distribution across age-groups than at present (29%, 37%, and 34%, respectively). Prevalence under age 15 years is predicted to rise from 94 000 in 2005, to 160 000 in 2020. INTERPRETATION If present trends continue, doubling of new cases of type 1 diabetes in European children younger than 5 years is predicted between 2005 and 2020, and prevalent cases younger than 15 years will rise by 70%. Adequate health-care resources to meet these childrens needs should be made available. FUNDING European Community Concerted Action Program.

Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes

Aims/hypothesisAlthough ischaemic heart disease is the predominant cause of mortality in older people with diabetes, age-specific mortality rates have not been published for patients with Type 1 diabetes. The Diabetes UK cohort, essentially one of patients with Type 1 diabetes, now has sufficient follow-up to report all heart disease, and specifically ischaemic heart disease, mortality rates by age.MethodsA cohort of 23,751 patients with insulin-treated diabetes, diagnosed under the age of 30 years and from throughout the United Kingdom, was identified during the period 1972 to 1993 and followed for mortality until December 2000. Age- and sex-specific heart disease mortality rates and standardised mortality ratios were calculated.ResultsThere were 1437 deaths during the follow-up, 536 from cardiovascular disease, and of those, 369 from ischaemic heart disease. At all ages the ischaemic heart disease mortality rates in the cohort were higher than in the general population. Mortality rates within the cohort were similar for men and women under the age of 40. The standardised mortality ratios were higher in women than men at all ages, and in women were 44.8 (95%CI 20.5–85.0) at ages 20–29 and 41.6 (26.7–61.9) at ages 30–39.Conclusions/interpretationThe risk of mortality from ischaemic heart disease is exceptionally high in young adult women with Type 1 diabetes, with rates similar to those in men with Type 1 diabetes under the age of 40. These observations emphasise the need to identify and treat coronary risk factors in these young patients.

The British Diabetic Association Cohort Study, II: cause‐specific mortality in patients with insulin‐treated diabetes mellitus

Aims To assess mortality in patients with diabetes incident under the age of 30 years.

Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE study

EURODIAB ACE is a collaborative European study that was set up to assess incidence of childhood insulin-dependent diabetes mellitus (IDDM) in Europe, test the proposal of a south-north gradient, and to gather information to determine the causes and pathogenesis of the disease. Here, the basic epidemiological results are reported. Newly diagnosed cases of IDDM in children aged up to 15 years were identified prospectively in twenty-four geographically well-defined study regions in Europe and Israel (a total of 16.8 million children) during 1989 and 1990. 3060 cases were identified with estimated ascertainment rates exceeding 90% in all study regions. Age-standardised and sex-standardised incidence rates varied widely, ranging from 4.6 (northern Greece) to 42.9 (two regions in Finland) cases per 100,000 per year. Rates in southern Europe were generally higher than previously assumed, and there was an unexpectedly high incidence in Sardinia, which had the second highest rate (30.2 cases per 100,000 per year) recorded in Europe. Eastern European regions had generally low rates. The collaborative network now established provides a framework for further studies to examine the complex interaction between genetic and environmental factors in the cause and pathogenesis of IDDM.

Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies

Aims/hypothesisThe aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the published literature and performing a meta-analysis with adjustment for recognised confounders.MethodsAfter MEDLINE, Web of Science and EMBASE searches, crude ORs and 95% CIs for type 1 diabetes in children born by Caesarean section were calculated from the data reported in each study. Authors were contacted to facilitate adjustments for potential confounders, either by supplying raw data or calculating adjusted estimates. Meta-analysis techniques were then used to derive combined ORs and to investigate heterogeneity between studies.ResultsTwenty studies were identified. Overall, there was a significant increase in the risk of type 1 diabetes in children born by Caesarean section (OR 1.23, 95% CI 1.15–1.32, p < 0.001). There was little evidence of heterogeneity between studies (p = 0.54). Seventeen authors provided raw data or adjusted estimates to facilitate adjustments for potential confounders. In these studies, there was evidence of an increase in diabetes risk with greater birthweight, shorter gestation and greater maternal age. The increased risk of type 1 diabetes after Caesarean section was little altered after adjustment for gestational age, birth weight, maternal age, birth order, breast-feeding and maternal diabetes (adjusted OR 1.19, 95% CI 1.04–1.36, p = 0.01).Conclusions/interpretationThis analysis demonstrates a 20% increase in the risk of childhood-onset type 1 diabetes after Caesarean section delivery that cannot be explained by known confounders.

Trends in childhood type 1 diabetes incidence in Europe during 1989–2008: evidence of non-uniformity over time in rates of increase

Aims/hypothesisThe aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989–1998) and second (1999–2008) halves of the period.MethodsAll registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture–recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied.ResultsAscertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half.Conclusions/interpretationThe incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3–4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Worldwide childhood type 1 diabetes incidence--what can we learn from epidemiology?

Abstract:  Type 1 diabetes is the most common form of diabetes in most part of the world, although reliable data are still unavailable in several countries. Wide variations exist between the incidence rates of different populations, incidence is lowest in China and Venezuela (0.1 per 100 000 per year) and highest in Finland and Sardinia (37 per 100 000 per year). In most populations girls and boys are equally affected. In general, the incidence increases with age, the incidence peak is at puberty. After the pubertal years, the incidence rate significantly drops in young women, but remains relatively high in young adult males up to the age 29–35 years. Prospective national and large international registries (DIAMOND and EURODIAB) demonstrated an increasing trend in incidence in most regions of the world over the last few decades and increases seem to be the highest in the youngest age group. Analytical epidemiological studies have identified environmental risk factors operating early in life which might have contributed to the increasing trend in incidence. These include enteroviral infections in pregnant women, older maternal age (39–42 years), preeclampsia, cesarean section delivery, increased birthweight, early introduction of cow’s milk proteins and an increased rate of postnatal growth (weight and height). Optimal vitamin D supplementation during early life has been shown to be protective. Some of these environmental risk factors such as viruses may initiate autoimmunity toward the beta cell, other exposures may put on overload on the already affected beta cell and thus accelerate the disease process.

Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke? The Caerphilly Study

Background— Few studies have examined whether hemostatic markers contribute to risk of coronary disease and ischemic stroke independently of conventional risk factors. This study examines 11 hemostatic markers that reflect different aspects of the coagulation process to determine which have prognostic value after accounting for conventional risk factors. Methods and Results— A total of 2398 men aged 49 to 65 years were examined in 1984 to 1988, and the majority gave a fasting blood sample for assay of lipids and hemostatic markers. Men were followed up for a median of 13 years, and cardiovascular disease (CVD) events were recorded. There were 486 CVD events in total, 353 with prospective coronary disease and 133 with prospective ischemic stroke. On univariable analysis, fibrinogen, low activated protein C ratio, D-dimer, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were associated significantly with risk of CVD. On multivariable analyses with conventional risk factors forced into the proportional hazards model, fibrinogen, D-dimer, and PAI-1 were significantly associated with risk of CVD, whereas factor VIIc showed an inverse association (P=0.001). In a model that contained the conventional risk factors, the hazard ratio for subsequent CVD in the top third of the distribution of predicted risk relative to the bottom third was 2.7 for subjects without preexisting CVD. This ratio increased to 3.7 for the model that also contained the 4 hemostatic factors. Conclusions— Fibrinogen, D-dimer, PAI-1 activity, and factor VIIc each has potential to increase the prediction of coronary disease/ischemic stroke in middle-aged men, in addition to conventional risk factors.

Moderately Elevated Plasma Homocysteine, Methylenetetrahydrofolate Reductase Genotype, and Risk for Stroke, Vascular Dementia, and Alzheimer Disease in Northern Ireland

Background and Purpose— Elevated plasma homocysteine level has been associated with increased risk for cardiovascular and cerebrovascular disease. Variation in the levels of this amino acid has been shown to be due to nutritional status and methylenetetrahydrofolate reductase (MTHFR) genotype. Methods— Under a case-control design we compared fasting levels of homocysteine and MTHFR genotypes in groups of subjects consisting of stroke, vascular dementia (VaD), and Alzheimer disease patients and normal controls from Northern Ireland. Results— A significant increase in plasma homocysteine was observed in all 3 disease groups compared with controls. This remained significant after allowance for confounding factors (age, sex, hypertension, cholesterol, smoking, creatinine, and nutritional measures). MTHFR genotype was not found to influence homocysteine levels, although the T allele was found to increase risk for VaD and perhaps dementia after stroke. Conclusions— We report that moderately high plasma levels of homocysteine are associated with stroke, VaD, and Alzheimer disease. This is not due to vascular risk factors, nutritional status, or MTHFR genotype.

Association between polymorphism in regulatory region of gene encoding tumour necrosis factor α and risk of Alzheimer's disease and vascular dementia: a case-control study

Summary Background Deposition of β-amyloid in the brains of patients with Alzheimers disease is thought to precede a chain of events that leads to an inflammatory response by the brain. We postulated that genetic variation in the regulatory region of the gene for the proinflammatory cytokine tumour necrosis factor α (TNF-α) leads to increased risk of Alzheimers disease and vascular dementia. Methods A polymorphism in the regulatory region of the TNF- α gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimers disease, 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. These groups of individuals were also genotyped for the apolipoprotein E polymorphism, and the vascular dementia and stroke groups were typed at the HLADR locus. Findings The distribution of TNF-α genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2·51 (95% CI 1·49–4·21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that the possession of the T allele significantly increased the risk of Alzheimers disease associated with carriage of the apolipoprotein ɛ4 allele (odds ratio 2·73 [1·68–4·44] for those with apolipoprotein E ɛ4 but no TNF-α T, vs 4·62 [2·38–8·96] for those with apolipoprotein E ɛin;4 and TNF-α T; p=0·03). Interpretation Possession of the TNF-α T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimers disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimers disease, and perhaps especially in patients who have had a stroke.