Real-world study of the concomitant use of biphasic insulin aspart 30/70 with GLP-1 receptor agonist versus first-generation basal insulin with GLP-1 receptor agonist in type 2 diabetes.

AIMS: Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1RA) to treat type 2 diabetes (T2D) is common. While many studies have investigated concomitant therapy with basal insulin+GLP-1RA, few have reported on premixed insulin+GLP-1RA. We aimed to address this gap using data from the Clinical Practice Research Datalink Aurum database in England. METHODS: This retrospective cohort study with propensity score matching assessed glycaemic levels and other clinical outcomes in people with T2D, comparing biphasic insulin aspart 30/70 (BIAsp 30) + GLP-1RA with basal insulin (insulin detemir/glargine U100) + GLP-1RA (from 2006 to 2021). RESULTS: In total, 4770 eligible people were identified; 1511 had a BIAsp 30 + GLP-1RA regimen and were propensity score-matched to an equal number receiving basal+GLP-1RA. There was no significant difference in glycated haemoglobin (HbA1c) reduction between cohorts at 6 months (p = 0.15), with a decrease of -1.07 (95% CI: -1.16; -0.98) %-points (-11.7 mmol/mol [95% CI: -12.7; -10.7]) in the BIAsp 30 + GLP-1RA cohort, versus -0.97 (95% CI: -1.07; -0.88) %-points (-10.6 mmol/mol [95% CI: -11.7; -9.6]) in the basal+GLP-1RA cohort. Body mass index (BMI) decreased by -0.35 kg/m2 (95% CI: -0.52;-0.18) at 6 months with BIAsp 30 + GLP-1RA, versus -0.72 kg/m2 (95% CI: -0.90;-0.54) with basal+GLP-1RA (p = 0.003). BMI was influenced by the initiation sequence of GLP-1RA in relation to insulin (p < 0.0001). Hypoglycaemia rates were low and not significantly different between cohorts. CONCLUSIONS: Combining BIAsp 30 + GLP-1RA provides glycaemic control with no significant difference to that of propensity score-matched people receiving basal insulin+GLP-1RA, with no increase in hypoglycaemia risk or weight gain.

Fetal Overgrowth and Preterm Delivery in Women With Type 1 Diabetes Using Insulin Pumps or Multiple Daily Injections: A Post Hoc Analysis of the EVOLVE Study Cohort.

OBJECTIVE: To compare the risk of fetal overgrowth and preterm delivery in pregnant women with type 1 diabetes (T1D) treated with insulin pumps versus multiple daily injections (MDI) and examine whether possible differences were mediated through improved glycemic control or gestational weight gain during pregnancy. RESEARCH DESIGN AND METHODS: The risk of pregnancy and perinatal outcomes were evaluated in a cohort of 2,003 pregnant women with T1D enrolled from 17 countries in a real-world setting during 2013-2018. RESULTS: In total, 723 women were treated with pumps and 1,280 with MDI. At inclusion (median gestational weeks 8.6 [interquartile range 7-10]), pump users had lower mean HbA1c (mean ± SD 50.6 ± 9.8 mmol/mol [6.8 ± 0.9%] vs. 53.6 ± 13.8 mmol/mol [7.1 ± 1.3%], P < 0.001), longer diabetes duration (18.4 ± 7.8 vs. 14.4 ± 8.2 years, P < 0.001), and higher prevalence of retinopathy (35.3% vs. 24.4%, P < 0.001). Proportions of large for gestational age (LGA) offspring and preterm delivery were 59.0% vs. 52.2% (adjusted odds ratio [OR] 1.36 [95% CI 1.09; 1.70], P = 0.007) and 39.6% vs. 32.1% (adjusted OR 1.46 (95% CI 1.17; 1.82), P < 0.001), respectively. The results did not change after adjustment for HbA1c or gestational weight gain. CONCLUSIONS: Insulin pump treatment in pregnant women with T1D, prior to the widespread use of continuous glucose monitoring or automated insulin delivery, was associated with a higher risk of LGA offspring and preterm delivery compared with MDI in crude and adjusted analyses. This association did not appear to be mediated by differences in glycemic control as represented by HbA1c or by gestational weight gain.

Real-world study of ethnic differences in glycaemic control and clinical characteristics among insulin-naïve people with type 2 diabetes initiating biphasic insulin aspart 30/70: A retrospective, observational cohort study in England.

AIMS: This study investigated the ethnic differences in glycaemic levels and clinical characteristics among insulin-naïve people with type 2 diabetes (T2D) initiating biphasic insulin aspart 30/70 (BIAsp 30) in primary practice in England. MATERIALS AND METHODS: Retrospective, observational cohort study utilizing data from the Clinical Practice Research Datalink Aurum database, including White, South Asian, Black and Chinese insulin-naïve adults with T2D, initiating BIAsp 30. The index date was that of the first BIAsp 30 prescription. Endpoints included change in glycated haemoglobin (HbA1c) and body mass index (BMI) 6 months post index. RESULTS: In total, 11 186 eligible people were selected (9443 White, 1116 South Asian, 594 Black, 33 Chinese). HbA1c decreased across all subgroups 6 months post index: estimated %-point changes [95% CI of -2.32 (-2.36; -2.28) (White); -1.91 (-2.02; -1.80) (South Asian); -2.55 (-2.69; -2.40) (Black); and -2.64 (-3.24; -2.04) (Chinese)]. The BMI increased modestly 6 months post index in all subgroups [estimated changes (95% CI) kg/m2 : White, 0.92 (0.86; 0.99); South Asian, 0.60 (0.41; 0.78); Black, 1.41 (1.16; 1.65); and Chinese, 0.32 (-0.67; 1.30)]. In the overall population, hypoglycaemic event rates increased from 0.92 events per 100 patient-years before the index to 3.37 events per 100 patient-years post index; event numbers were too low to be analysed by subgroup. CONCLUSIONS: Among insulin-naïve people with T2D initiating BIAsp 30, clinically meaningful HbA1c reductions in all ethnicities were observed. Some ethnic groups had larger reductions than others, but differences were small. In all groups, small BMI increases were seen, with small differences observed between groups. Hypoglycaemia rates were low.

Obesity, cardiovascular risk and healthcare resource utilization in the UK.

AIMS: Obesity and cardiovascular diseases (CVDs) often co-occur, likely increasing the intensity of healthcare resource utilization (HCRU). This retrospective, observational database study examined the joint effect of obesity and cardiovascular risk status on HCRU and compared HCRU between body mass index (BMI) categories and CVD-risk categories in the UK. METHODS: Patient demographics and data on CVD and BMI were obtained from the UK Clinical Practice Research Datalink. Cardiovascular risk status, calculated using the Framingham Risk Equation, was used to categorize people into high-risk and low-risk groups, while a CVD diagnosis was used to define the established CVD group. Patients were split into BMI categories using the standard World Health Organization classifications. For each CVD and BMI category, mean number and costs of general practitioner contacts, hospital admissions and prescriptions were estimated. RESULTS: The final study population included 1,600,709 patients. Data on CVD status were available on just over one-quarter of the sample (28.6%) and BMI data for just less than half (43.2%). The number of general practitioner contacts and prescriptions increased with increasing BMI category for each of the three CVD-risk groups. The group with established CVD had the greatest utilization of all components of healthcare resource, followed by high CVD risk then low CVD-risk groups. CONCLUSION: Increasing BMI category and CVD-risk status both affected several HCRU components. These findings highlight the importance of timely obesity management and treatment of CVD-risk factors as a means of preventing increasing HCRU.

Long-Term Exposure to Wind Turbine Noise and Risk for Myocardial Infarction and Stroke: A Nationwide Cohort Study.

BACKGROUND: Noise from wind turbines (WTs) is reported as more annoying than traffic noise at similar levels, raising concerns as to whether WT noise (WTN) increases risk for cardiovascular disease, as observed for traffic noise. OBJECTIVES: We aimed to investigate whether long-term exposure to WTN increases risk of myocardial infarction (MI) and stroke. METHODS: We identified all Danish dwellings within a radius 20 times the height of the closest WT and 25% of the dwellings within [Formula: see text] the height of the closest WT. Using data on WT type and simulated hourly wind at each WT, we estimated hourly outdoor and low frequency (LF) indoor WTN for each dwelling and derived 1-y and 5-y running nighttime averages. We used hospital and mortality registries to identify all incident cases of MI ([Formula: see text]) and stroke ([Formula: see text]) among all adults age 25-85 y ([Formula: see text]), who lived in one of these dwellings for [Formula: see text] over the period 1982-2013. We used Poisson regression to estimate incidence rate ratios (IRRs) adjusted for individual- and area-level covariates. RESULTS: IRRs for MI in association with 5-y nighttime outdoor WTN [Formula: see text] (vs. [Formula: see text]) dB(A) and indoor LF WTN [Formula: see text] (vs. [Formula: see text]) dB(A) were 1.21 [95% confidence interval (CI): 0.91, 1.62; 47 exposed cases] and 1.29 (95% CI: 0.73, 2.28; 12 exposed cases), respectively. IRRs for intermediate categories of outdoor WTN [24-30, 30-36, and [Formula: see text] vs. [Formula: see text]] were slightly above the null and of similar size: 1.08 (95% CI: 1.04, 1.12), 1.07 (95% CI: 1.00, 1.12), and 1.06 (95% CI: 0.93, 1.22), respectively. For stroke, IRRs for the second and third outdoor exposure groups were similar to those for MI, but near or below the null for higher exposures. CONCLUSIONS: We did not find convincing evidence of associations between WTN and MI or stroke. https://doi.org/10.1289/EHP3340.

Impact of Long-Term Exposure to Wind Turbine Noise on Redemption of Sleep Medication and Antidepressants: A Nationwide Cohort Study.

BACKGROUND: Noise from wind turbines (WTs) is associated with annoyance and, potentially, sleep disturbances. OBJECTIVES: Our objective was to investigate whether long-term WT noise (WTN) exposure is associated with the redemption of prescriptions for sleep medication and antidepressants. METHODS: For all Danish dwellings within a radius of [Formula: see text] heights and for 25% of randomly selected dwellings within a radius of [Formula: see text] heights, we estimated nighttime outdoor and low-frequency (LF) indoor WTN, using information on WT type and simulated hourly wind. During follow-up from 1996 to 2013, 68,696 adults redeemed sleep medication and 82,373 redeemed antidepressants, from eligible populations of 583,968 and 584,891, respectively. We used Poisson regression with adjustment for individual and area-level covariates. RESULTS: Five-year mean outdoor nighttime WTN of [Formula: see text] was associated with a hazard ratio (HR) = 1.14 [95% confidence interval (CI]: 0.98, 1.33) for sleep medication and HR = 1.17 (95% CI: 1.01, 1.35) for antidepressants (compared with exposure to WTN of [Formula: see text]). We found no overall association with indoor nighttime LF WTN. In age-stratified analyses, the association with outdoor nighttime WTN was strongest among persons [Formula: see text] of age, with HRs (95% CIs) for the highest exposure group ([Formula: see text]) of 1.68 (1.27, 2.21) for sleep medication and 1.23 (0.90, 1.69) for antidepressants. For indoor nighttime LF WTN, the HRs (95% CIs) among persons [Formula: see text] of age exposed to [Formula: see text] were 1.37 (0.81, 2.31) for sleep medication and 1.34 (0.80, 2.22) for antidepressants. CONCLUSIONS: We observed high levels of outdoor WTN to be associated with redemption of sleep medication and antidepressants among the elderly, suggesting that WTN may potentially be associated with sleep and mental health. https://doi.org/10.1289/EHP3909.

Pregnancy exposure to wind turbine noise and adverse birth outcomes: a nationwide cohort study.

Noise from wind turbines (WTs) is reported as more annoying than traffic noise at similar levels, raising concerns as to whether WT noise (WTN) may negatively affect health, as reported for traffic noise. We aimed to investigate whether residential WTN is associated with adverse birth outcomes. Based on national registries, we identified all Danish dwellings situated within ≤ 20 wt heights radius and a random selection of 25% of dwellings situated within 20-40 wt heights radius of a WT. We identified 135,795 pregnant women living in the dwellings from 1982 to 2013, and collected information on gestational age and birth weight from a national birth registry. Using data on WT type and simulated hourly wind at each WT, we estimated hourly outdoor and low frequency (LF) indoor WTN at the dwellings of the pregnant women and aggregated as mean nighttime WTN during pregnancy. We used logistic regression with adjustment for individual and area-level covariates for the analyses. We did not find evidence suggesting that mean pregnancy or trimester-specific exposure to outdoor or indoor LF WTN were associated with any of the three adverse birth outcomes investigated: preterm birth (n = 13,003), term small for gestational age (n = 12,220) or term low birth weight (n = 1127). However, the number of cases in the highest exposure categories of ≥ 42 dB outdoor WTN or ≥ 15 dB indoor LF WTN were low for all outcomes (n between 0 and 31). The present study does not support an association between nighttime WTN and adverse birth outcomes. However, there were few cases in the high exposure groups and the results call for reproduction.

Long-term exposure to wind turbine noise and redemption of antihypertensive medication: A nationwide cohort study.

Noise from wind turbines (WTs) has been reported more annoying than traffic noise at similar levels, and concerns have been raised about whether WT noise (WTN) can increase risk for cardiovascular disease. We aimed to investigate if long-term exposure to WTN increases risk for hypertension, estimated as redemption of prescriptions for antihypertensive drugs. We identified all Danish dwellings within a radius of 20 WT heights from a WT and 25% randomly selected dwellings within 20-40 WT heights radius. Using data on WT type and hourly wind conditions at each WT, we estimated hourly outdoor (10-10,000 Hz) and low frequency (LF: 10-160 Hz) indoor WTN for all dwellings, and aggregated it as long-term nighttime running means. From nationwide registries, we identified 535,675 persons age 25-85 years living in these dwellings for >1 year from 1996 to 2013, of whom 83,729 fulfilled our case definition of redeeming ≥2 prescriptions and ≥180 defined daily doses of antihypertensive drugs within a year. Data were analyzed using Poisson regression according to categories of WTN exposure and adjustment for individual and area-level covariates. We found no associations between 5-year mean exposure to WTN during night and redemption of antihypertensives, with hazard ratios (HR) of 0.91 (95% confidence intervals (CI): 0.78-1.06) for outdoor WTN ≥ 42 dB(A) and of 1.06 (CI: 0.83-1.35) for indoor LF WTN ≥ 15 dB(A) when compared to the reference WTN levels (<24 dB(A) and <5 dB(A), respectively). The lack of association was consistent across sub-populations of people living on farms, far from major roads and with high validity of the noise estimate. For people younger than 65 years we found HRs of 0.81 (95% CI: 0.67-0.98) and 0.94 (95% CI: 0.68-1.30) for outdoor WTN ≥ 42 dB(A) and indoor WTN ≥ 15 dB(A), respectively, whereas for people above 65 years the corresponding HRs were 1.17 (95% CI: 0.90-1.52) and 1.28 (95% CI: 0.87-1.88). In conclusion, the present study does not support an association between WTN and redemption of antihypertensive medication.

Small-scale geographical variation in multiple sclerosis: A case-control study using Danish register data 1971-2013.

BACKGROUND: The aetiology of multiple sclerosis (MS) is largely unknown, but commonly assumed to be a complex interaction between genes and environmental exposures, presumably during early life. To evaluate the possible importance and timing of environmental exposures we investigated the spatial variation in the risk of MS in Denmark according to residence at birth, age 15, and clinical onset of disease. METHODS: We carried out a nationwide, register-based case-control study including 12 993 Danish MS cases with onset of disease 1971-2013. Information on exact residential addresses was available for all study subjects in the Danish Civil Registration System. The spatial variation in risk of MS was estimated by kernel regression. RESULTS: We identified spatial variation in the risk of MS according to residence at birth, age 15, and onset of disease. Several high- and low-risk areas were identified across the country with some variation between birth, age 15, and onset. CONCLUSIONS: Small-scale geographical variation in the risk of MS suggests that local environmental risk factors could be at play and may be related to life style factors.

Long-term exposure to wind turbine noise at night and risk for diabetes: A nationwide cohort study.

Focus on renewable energy sources and reduced unit costs has led to increased number of wind turbines (WTs). WT noise (WTN) is reported to be highly annoying at levels from 30 to 35 dB and up, whereas for traffic noise people report to be highly annoyed from 40 to 45 dB and up. This has raised concerns as to whether WTN may increase risk for major diseases, as exposure to traffic noise has consistently been associated with increased risk of cardiovascular disease and diabetes. We identified all Danish dwellings within a radius of 20 WT heights and 25% of all dwellings within 20-40 WT heights from a WT. Using detailed data on WT type and hourly wind data at each WT position and height, we estimated hourly outdoor and low frequency indoor WTN for all dwellings, aggregated as nighttime 1- and 5-year running means. Using nationwide registries, we identified a study population of 614,731 persons living in these dwellings in the period from 1996 to 2012, of whom 25,148 developed diabetes. Data were analysed using Poisson regression with adjustment for individual and area-levels covariates. We found no associations between long-term exposure to WTN during night and diabetes risk, with incidence rate ratios (IRRs) of 0.90 (95% confidence intervals (CI): 0.79-1.02) and 0.92 (95% CI: 0.68-1.24) for 5-year mean nighttime outdoor WTN of 36-42 and ≥ 42 dB, respectively, compared to < 24 dB. For 5-year mean nighttime indoor low frequency WTN of 10-15 and ≥ 15 dB we found IRRs of 0.90 (0.78-1.04) and 0.74 (95% CI: 0.41-1.34), respectively, when compared to and < 5 dB. The lack of association was consistent across strata of sex, distance to major road, validity of noise estimate and WT height. The present study does not support an association between nighttime WTN and higher risk of diabetes. However, there were only few cases in the highest exposure groups and findings need reproduction.

Short-term nighttime wind turbine noise and cardiovascular events: A nationwide case-crossover study from Denmark.

AIMS: The number of people exposed to wind turbine noise (WTN) is increasing. WTN is reported as more annoying than traffic noise at similar levels. Long-term exposure to traffic noise has consistently been associated with cardiovascular disease, whereas effects of short-term exposure are much less investigated due to little day-to-day variation of e.g. road traffic noise. WTN varies considerably due to changing weather conditions allowing investigation of short-term effects of WTN on cardiovascular events. METHODS AND RESULTS: We identified all hospitalisations and deaths from stroke (16,913 cases) and myocardial infarction (MI) (17,559 cases) among Danes exposed to WTN between 1982 and 2013. We applied a time-stratified, case-crossover design. Using detailed data on wind turbine type and hourly wind data at each wind turbine, we simulated mean nighttime outdoor (10-10,000 Hz) and nighttime low frequency (LF) indoor WTN (10-160 Hz) over the 4 days preceding diagnosis and reference days. For indoor LF WTN between 10 and 15 dB(A) and above 15 dB(A), odds ratios (ORs) for MI were 1.27 (95% confidence interval (CI): 0.97-1.67; cases = 198) and 1.62 (95% CI: 0.76-3.45; cases = 21), respectively, when compared to indoor LF WTN below 5 dB(A). For stroke, corresponding ORs were 1.17 (95% CI: 0.95-1.69; cases = 166) and 2.30 (95% CI: 0.96-5.50; cases = 15). The elevated ORs above 15 dB(A) persisted across sensitivity analyses. When looking at specific lag times, noise exposure one day before MI events and three days before stroke events were associated with the highest ORs. For outdoor WTN at night, we observed both increased and decreased risk estimates. CONCLUSION: This study did not provide conclusive evidence of an association between WTN and MI or stroke. It does however suggest that indoor LF WTN at night may trigger cardiovascular events, whereas these events seemed largely unaffected by nighttime outdoor WTN. These findings need reproduction, as they were based on few cases and may be due to chance.

Investigation of spatio-temporal cancer clusters using residential histories in a case-control study of non-Hodgkin lymphoma in the United States.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is an enigmatic disease with few known risk factors. Spatio-temporal epidemiologic analyses have the potential to reveal patterns that may give clues to new risk factors worthy of investigation. We sought to investigate clusters of NHL through space and time based on life course residential histories. METHODS: We used residential histories from a population-based NHL case-control study of 1300 cases and 1044 controls with recruitment centers in Iowa, Detroit, Seattle, and Los Angeles, and diagnosed in 1998-2000. Novel methods for cluster detection allowing for residential mobility, called Q-statistics, were used to quantify nearest neighbor relationships through space and time over the life course to identify cancer clusters. Analyses were performed on all cases together and on two subgroups of NHL: Diffuse large B-cell lymphoma and follicular lymphoma. These more homogenous subgroups of cases might have a more common etiology that could potentially be detected in cluster analysis. Based on simulation studies designed to help account for multiple testing across space and through time, we required at least four significant cases nearby one another to declare a region a potential cluster, along with confirmatory analyses using spatial-only scanning windows (SaTScan). RESULTS: Evidence of a small cluster in southeastern Oakland County, MI was suggested using residences 10-18 years prior to diagnosis, and confirmed by SaTScan in a time-slice analysis 20 years prior to diagnosis, when all cases were included in the analysis. Consistent evidence of clusters was not seen in the two histologic subgroups. CONCLUSIONS: Suggestive evidence of a small space-time cluster in southeastern Oakland County, MI was detected in this NHL case-control study in the USA.

Long-term exposure to low-level arsenic in drinking water and diabetes incidence: a prospective study of the diet, cancer and health cohort.

BACKGROUND: Established causes of diabetes do not fully explain the present epidemic. High-level arsenic exposure has been implicated in diabetes risk, but the effect of low-level arsenic exposure in drinking water remains unclear. OBJECTIVE: We sought to determine whether long-term exposure to low-level arsenic in drinking water in Denmark is associated with an increased risk of diabetes using a large prospective cohort. METHODS: During 1993-1997, we recruited 57,053 persons. We followed each cohort member for diabetes occurrence from enrollment until 31 December 2006. We traced and geocoded residential addresses of the cohort members and used a geographic information system to link addresses with water-supply areas. We estimated individual exposure to arsenic using all addresses from 1 January 1971 until the censoring date. Cox proportional hazards models were used to model the association between arsenic exposure and diabetes incidence, separately for two definitions of diabetes: all cases and a more strict definition in which cases of diabetes based solely on blood glucose results were excluded. RESULTS: Over a mean follow-up period of 9.7 years for 52,931 eligible participants, there were a total of 4,304 (8.1%) diabetes cases, and 3,035 (5.8%) cases of diabetes based on the more strict definition. The adjusted incidence rate ratios (IRRs) per 1-µg/L increment in arsenic levels in drinking water were as follows: IRR = 1.03 (95% CI: 1.01, 1.06) and IRR = 1.02 (95% CI: 0.99, 1.05) for all and strict diabetes cases, respectively. CONCLUSIONS: Long-term exposure to low-level arsenic in drinking water may contribute to the development of diabetes.

Space-time clusters of breast cancer using residential histories: a Danish case-control study.

BACKGROUND: A large proportion of breast cancer cases are thought related to environmental factors. Identification of specific geographical areas with high risk (clusters) may give clues to potential environmental risk factors. The aim of this study was to investigate whether clusters of breast cancer existed in space and time in Denmark, using 33 years of residential histories. METHODS: We conducted a population-based case-control study of 3138 female cases from the Danish Cancer Registry, diagnosed with breast cancer in 2003 and two independent control groups of 3138 women each, randomly selected from the Civil Registration System. Residential addresses of cases and controls from 1971 to 2003 were collected from the Civil Registration System and geo-coded. Q-statistics were used to identify space-time clusters of breast cancer. All analyses were carried out with both control groups, and for 66% of the study population we also conducted analyses adjusted for individual reproductive factors and area-level socioeconomic indicators. RESULTS: In the crude analyses a cluster in the northern suburbs of Copenhagen was consistently found throughout the study period (1971-2003) with both control groups. When analyses were adjusted for individual reproductive factors and area-level socioeconomic indicators, the cluster area became smaller and less evident. CONCLUSIONS: The breast cancer cluster area that persisted after adjustment might be explained by factors that were not accounted for such as alcohol consumption and use of hormone replacement therapy. However, we cannot exclude environmental pollutants as a contributing cause, but no pollutants specific to this area seem obvious.

Performance of cancer cluster Q-statistics for case-control residential histories.

Few investigations of health event clustering have evaluated residential mobility, though causative exposures for chronic diseases such as cancer often occur long before diagnosis. Recently developed Q-statistics incorporate human mobility into disease cluster investigations by quantifying space- and time-dependent nearest neighbor relationships. Using residential histories from two cancer case-control studies, we created simulated clusters to examine Q-statistic performance. Results suggest the intersection of cases with significant clustering over their life course, Q(i), with cases who are constituents of significant local clusters at given times, Q(it), yielded the best performance, which improved with increasing cluster size. Upon comparison, a larger proportion of true positives were detected with Kulldorf's spatial scan method if the time of clustering was provided. We recommend using Q-statistics to identify when and where clustering may have occurred, followed by the scan method to localize the candidate clusters. Future work should investigate the generalizability of these findings.

Cancer in first-degree relatives and risk of testicular cancer in Denmark.

Familial aggregation of testicular cancer has been reported consistently, but it is less clear if there is any association between risk of testicular cancer and other cancers in the family. We conducted a population-based case-control study to examine the relationship between risk of testicular cancer and 22 different cancers in first-degree relatives. We included 3,297 cases of testicular cancer notified to the Danish Cancer Registry between 1991 and 2003. A total of 6,594 matched controls were selected from the Danish Civil Registration System, which also provided the identity of 40,104 first-degree relatives of case and controls. Familial cancer was identified by linkage to the Danish Cancer Registry, and we used conditional logistic regression to analyze whether cancer among first-degree relatives was associated with higher risk of testicular cancer. Rate ratio for testicular cancer was 4.63 (95% CI: 2.41-8.87) when a father, 8.30 (95% CI: 3.81-18.10) when a brother and 5.23 (95% CI: 1.35-20.26) when a son had testicular cancer compared to no familial testicular cancer. Results were similar when analyses were stratified by histologic subtypes of testicular cancer. Familial non-Hodgkin lymphoma and esophageal cancer were associated with testicular cancer; however, these may be chance findings. The familial aggregation of testicular and possibly other cancers may be explained by shared genes and/or shared environmental factors, but the mutual importance of each of these is difficult to determine.