Space-Time Clustering of Non-Hodgkin Lymphoma Using Residential Histories in a Danish Case-Control Study

Non-Hodgkin lymphoma (NHL) is a frequent cancer and incidence rates have increased markedly during the second half of the 20^th century; however, the few established risk factors cannot explain this rise and still little is known about the aetiology of NHL. Spatial analyses have been applied in an attempt to identify environmental risk factors, but most studies do not take human mobility into account. The aim of this study was to identify clustering of NHL in space and time in Denmark, using 33 years of residential addresses. We utilised the nation-wide Danish registers and unique personal identification number that all Danish citizens have to conduct a register-based case-control study of 3210 NHL cases and two independent control groups of 3210 each. Cases were identified in the Danish Cancer Registry and controls were matched by age and sex and 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 geocoded. Data on pervious hospital diagnoses and operations were obtained from the National Patient Register. We applied the methods of the newly developed Q-statistics to identify space-time clustering of NHL. All analyses were conducted with each of the two control groups, and we adjusted for previous history of autoimmune disease, HIV/AIDS or organ transplantation. Some areas with statistically significant clustering were identified; however, results were not consistent across the two control groups; thus we interpret the results as chance findings. We found no evidence for clustering of NHL in space and time using 33 years of residential histories, suggesting that if the rise in incidence of NHL is a result of risk factors that vary across space and time, the spatio-temporal variation of such factors in Denmark is too small to be detected with the applied method.     

Risk of testicular cancer in subfertile men: case-control study

ObjectiveTo evaluate the association between subfertility in men and the subsequent risk of testicular cancer.DesignPopulation based case-control study.SettingThe Danish population.ParticipantsCases were identified in the Danish Cancer Registry; controls were randomly selected from the Danish population with the computerised Danish Central Population Register. Men were interviewed by telephone; 514 men with cancer and 720 controls participated.ResultsA reduced risk of testicular cancer was associated with paternity (relative risk 0.63; 95% confidence interval 0.47 to 0.85). In men who before the diagnosis of testicular cancer had a lower number of children than expected on the basis of their age, the relative risk was 1.98 (1.43 to 2.75). There was no corresponding protective effect associated with a higher number of children than expected. The associations were similar for seminoma and non-seminoma and were not influenced by adjustment for potential confounding factors.ConclusionThese data are consistent with the hypothesis that male subfertility and testicular cancer share important aetiological factors.

Key messages

• The incidence of testicular cancer has increased in the past 50 years, and there is some evidence to suggest that sperm quality has decreased in the same period
• It has been hypothesised that common aetiological factors may exist for testicular cancer and for male subfertility
• The association between male subfertility and subsequent risk of testicular cancer is strong and consistent with the hypothesis of a common aetiology
• The association is similar for seminoma and non-seminoma, and it persists when several potentially confounding factors are taken into account

     

Elevated residential exposure to power frequency magnetic field associated with greater average age at diagnosis for patients with brain tumors

To explore whether the age at cancer diagnosis was associated with residential exposure to magnetic field, we compared average ages at diagnosis for cases of leukemia, brain tumor, or female breast cancer with elevated exposure (magnetic flux density >or= 0.2 microT, or residential distance from major power lines 100 m from major power lines). Comparing with brain tumor cases with background magnetic field exposure (n = 506), brain tumor cases with elevated exposure (n = 71) were 6 years older on average at diagnosis (P = 0.01). The difference was greater for males (45.2 vs. 52.1 years, P = 0.01) than for females (44.3 vs. 48.2 years, P = 0.27). No such phenomena at a significant level was observed for leukemia, female breast cancer, or a random sample of general population. We noted an association between magnetic field exposure and a greater mean age at diagnosis for brain tumors. Whether or not these phenomena suggest a delayed occurrence of brain tumors following a higher than background residential magnetic field exposure deserves further investigation.     

Frailty modelling of testicular cancer incidence using Scandinavian data

The incidence of testicular cancer is highest among young men, and then decreases sharply with age. This points towards a frailty effect, where some men have a much greater risk of testicular cancer than the majority of the male population. Those with the highest risk get cancer, drain the group of individuals at risk, and leave a healthy male population which has approximately zero risk of testicular cancer. This leads to the observed decrease in incidence. We discuss a frailty model, where the frailty is compound-Poisson-distributed. This allows for a non-susceptible group (of zero frailty). The model is successfully applied to incidence data from the Danish and Norwegian registries. It is indicated that there was a decrease in incidence for males born during World War II in both countries. Bootstrap analysis is used to find the degree of variation in the estimates. In the Armitage-Doll multistage model, the estimated number of transitions needed for a cell to become malignant is close to 3 for non-seminomas and 4 for seminomas in both the Danish and Norwegian data. This paper demonstrates that a model including a frailty effect fits the incidence data well and gives interesting results and interpretations, although this is no proof of the effect's truth.     

Residential sunlight exposure is associated with a decreased risk of prostate cancer

The possibility that exposure to sunlight reduces the risk of clinical prostate cancer has been strongly suggested by ecologic data. However, data on prostate cancer risk in relation to sunlight exposure in individuals are sparse. We analyzed data from the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study in order to test the hypothesis that residential sunlight exposure reduces the risk of prostate cancer. We identified 153 men with incident prostate cancer from a cohort of 3414 white men who completed the baseline interview and dermatologic examination in 1971-1975 and were followed up to 1992. We used Cox proportional hazards modeling to estimate relative risks (RR) and 95% confidence intervals (CI) for measures of residential sunlight exposure, adjusting for age, family history of prostate cancer, and dietary intake of fat and calcium. Residence in the South at baseline (RR = 0.68, CI = 0.41-1.13), state of longest residence in the South (RR = 0.62, CI = 0.40-0.95), and high solar radiation in the state of birth (RR = 0.49, CI = 0.30-0.79) were associated with significant and substantial reductions in prostate cancer risk. These data support the hypothesis that sunlight exposure reduces the risk of prostate cancer and have important implications for prostate cancer prevention.     

Widespread nasal carriage of Mycobacterium leprae among a healthy population in a hyperendemic region of northeastern Brazil

A case-control study was conducted to determine the presence of Mycobacterium leprae DNA in nasal secretions of leprosy cases and nonleprosy individuals in Fortaleza, Brazil. It included 185 cases identified by physicians at the Dona Libânia National Reference Centre for Sanitary Dermatology (CDERM). A control group (Co) (n = 136) was identified among individuals from CDERM not diagnosed as leprosy cases. To augment the spatial analysis of M. leprae specific repetitive element (RLEP) positive prevalence, an external group (EG) (n = 121), a convenience sample of healthy students, were included. Polymerase chain reaction for the RLEP sequence was conducted for all participants. Prevalence of RLEP positivity for cases and Co were 69.2% and 66.9%, respectively, significantly higher than for EG (28.1%), and reported elsewhere. Male sex, belonging to a lower socioeconomic status (D/E), history of a previous contact with a case and being older, were associated with being a leprosy case. Our geographical analysis demonstrated that the bacillus is widespread among the healthy population, with clusters of RLEP positive multibacillary cases concentrated in distinct areas of the city. Our results suggest that in endemic areas, as in Fortaleza, surveillance for both nonhousehold leprosy contacts and members of the general population living in cluster areas should be implemented.     

Risk of testicular cancer after vasectomy: cohort study of over 73,000 men.

OBJECTIVE--To confirm or refute reports that vasectomy may increase the risk of cancers of the testis and prostate. DESIGN--Computerised record linkage study of cohort of men with vasectomy and comparison of cancer rates with those in the whole Danish population; manual check of all records of patients with testicular and prostate cancer diagnosed within the first year of follow up. SETTING--Denmark 1977-89. SUBJECTS--Cohort of 73,917 men identified in hospital discharge and pathology registers as having had a vasectomy for any reason during 1977-89. MAIN OUTCOME MEASURES--Observed incidences of testicular, prostate, and other cancers up to the end of 1989. RESULTS--The overall pattern of cancer incidence in the study cohort was similar to that expected nationally. No increased incidence in testicular cancer was observed (70 cases; standardised morbidity ratio 1.01 (95% confidence interval 0.79 to 1.28)). The incidence during the first year of follow up was also close to that expected (nine cases; standardised morbidity ratio 0.80 (0.36 to 1.51)). The incidence of prostate cancer was not increased (165 cases; standardised morbidity ratio 0.98 (0.84 to 1.14)). CONCLUSIONS--The incidence of testicular cancer in men with vasectomy is no higher than in other men. Vasectomy does not cause testicular cancer and does not accelerate the growth or diagnosis of pre-existing testicular neoplasms. Data concerning a causal relation between vasectomy and prostate cancer were inconclusive.     

The rising incidence of testicular cancer among young men in Canada,data from 1971–2015

BackgroundTesticular cancer is the most common malignancy among young men aged 15–44 in Canada. The goal of this analysis was to examine age-period-cohort effects of testicular cancer incidence between 1971 and 2015.MethodsData were collected from the National Cancer Incidence Reporting System and the Canadian Cancer Registry. Birth cohort models were fit using the National Cancer Institute’s web tool. Incidence annual percent changes were estimated using NCI’s Joinpoint Regression Program.ResultsIncidence of testicular cancer in Canada has increased steadily since 1971. A birth cohort effect was observed for men born in the years after 1945. The rate of testicular cancer peaks at age 35 and drops off with increasing age.ConclusionIncidence of testicular cancer has risen dramatically in Canada in recent decades and the cohort effect indicates the need to investigate exposures that have increased since 1945 and that may affect development in young men.     

Local Bladder Cancer Clusters in Southeastern Michigan Accounting for Risk Factors,Covariates and Residential Mobility

Background

In case control studies disease risk not explained by the significant risk factors is the unexplained risk. Considering unexplained risk for specific populations, places and times can reveal the signature of unidentified risk factors and risk factors not fully accounted for in the case-control study. This potentially can lead to new hypotheses regarding disease causation.

Methods

Global, local and focused Q-statistics are applied to data from a population-based case-control study of 11 southeast Michigan counties. Analyses were conducted using both year- and age-based measures of time. The analyses were adjusted for arsenic exposure, education, smoking, family history of bladder cancer, occupational exposure to bladder cancer carcinogens, age, gender, and race.

Results

Significant global clustering of cases was not found. Such a finding would indicate large-scale clustering of cases relative to controls through time. However, highly significant local clusters were found in Ingham County near Lansing, in Oakland County, and in the City of Jackson, Michigan. The Jackson City cluster was observed in working-ages and is thus consistent with occupational causes. The Ingham County cluster persists over time, suggesting a broad-based geographically defined exposure. Focused clusters were found for 20 industrial sites engaged in manufacturing activities associated with known or suspected bladder cancer carcinogens. Set-based tests that adjusted for multiple testing were not significant, although local clusters persisted through time and temporal trends in probability of local tests were observed.

Conclusion

Q analyses provide a powerful tool for unpacking unexplained disease risk from case-control studies. This is particularly useful when the effect of risk factors varies spatially, through time, or through both space and time. For bladder cancer in Michigan, the next step is to investigate causal hypotheses that may explain the excess bladder cancer risk localized to areas of Oakland and Ingham counties, and to the City of Jackson.     

Two regions in chromosome 19q13.2-3 are associated with risk of lung cancer

Lung cancer is the most common fatal cancer among Danish men, and the incidence rate is increasing among women. In a case-cohort study, we have investigated the occurrence of lung cancer in relation to a high-risk haplotype, previously identified for breast cancer among post-menopausal women, and in relation to the closely linked polymorphisms XPD Asp312Asn and Lys751Gln. Among 54220 members of a Danish prospective cohort study aged 50-64 at entry, 265 lung cancer cases were identified and a sub-cohort comprising 272 individuals was used for comparison. Among women in the 50-55 year age interval, homozygous carriers of the high-risk haplotype were at increased risk of lung cancer (RR=7.02, 95% CI=1.88-26.18). In the 56-60 year and 61-70 year age intervals, no associations were observed. Among men, no statistically significant associations were found in any age interval. Female homozygous carriers of the variant allele of XPD Lys751Gln were at significantly increased risk of lung cancer in the two younger age-intervals (50-55 years: RR=5.60, 95% CI=1.18-26.45, 56-60 years: RR=10.60, 95% CI=1.50-75.64). Among men, carriers of the variant allele of XPD Lys751Gln had a non-significantly increased risk of lung cancer in the youngest age interval (RR=6.38, 95% CI=0.74-54.90). When the polymorphisms in XPD Asp312Asn and Lys751Gln were mutually adjusted, XPD Asp312Asn was not associated with increased risk of cancer. We found no interaction between genotypes and duration of smoking. In conclusion, two regions of chromosome 19q13.2-3 seem to be associated with risk of lung cancer.     

Strategies for evaluating the environment-public health interaction of long-term latency disease: the quandary of the inconclusive case-control study

Environmental links to disease are difficult to uncover because environmental exposures are variable in time and space, contaminants occur in complex mixtures, and many diseases have a long time delay between exposure and onset. Furthermore, individuals in a population have different activity patterns (e.g., hobbies, jobs, and interests), and different genetic susceptibilities to disease. As such, there are many potential confounding factors to obscure the reasons that one individual gets sick and another remains healthy. An important method for deducing environmental associations with disease outbreak is the retrospective case-control study wherein the affected and control subject cohorts are studied to see what is different about their previous exposure history. Despite success with infectious diseases (e.g., food poisoning, and flu), case-control studies of cancer clusters rarely have an unambiguous outcome. This is attributed to the complexity of disease progression and the long-term latency between exposure and disease onset. In this article, we consider strategies for investigating cancer clusters and make some observations for improving statistical power through broader non-parametric approaches wherein sub-populations (i.e., whole towns), rather than individuals, are treated as the cases and controls, and the associated cancer rates are treated as the dependent variable. We subsequently present some ecological data for tungsten and cobalt from studies by University of Arizona researchers who document elevated levels of tungsten and cobalt in Fallon, NV. These results serve as candidates for future hybrid ecologic case-control investigations of childhood leukemia clusters.     

Common bottlenose dolphin (Tursiops truncatus) social structure and distribution changes following the 2008 Unusual Mortality Event in the Indian River Lagoon,Florida

In animal societies with fission-fusion dynamics, demographic disturbances can influence the social and spatial structure of the population. Within the Indian River Lagoon (IRL), Florida, common bottlenose dolphins (Tursiops truncatus) have experienced recurrent unusual mortality events (UMEs) providing an opportunity to examine postdisturbance population and social cluster restructuring. This study investigates the impact of the potentially nonepizootic 2008 UME on the IRL dolphin population. Photo-identification surveys conducted from August 2006 to May 2010 were stratified into pre- (August 2006–April 2008) and post-UME (September 2008–May 2010) time periods. Social network and spatial (univariate kernel density) analyses were limited to individuals sighted 5+ times per period (pre-UME = 183, post-UME = 134), and indicated a change from 11 to ten social clusters, although individuals did not always reassociate with pre-UME cluster associates. Despite the social and spatial disconnect between IRL proper and Mosquito Lagoon clusters, both network density and core area spatial overlap increased post-UME allowing for increased intercluster interactions. However, intracluster associations increased as well, allowing the population to maintain multiple social clusters within a loosely connected network. This study shows the important role sociality may play in the adaptability of cetaceans to environmental and demographic changes.     

Prevalence of carcinoma in situ of the testis in 207 oligozoospermic men from infertile couples: prospective study of testicular biopsies.

OBJECTIVE: To investigate the prevalence of carcinoma in situ of the testis in a group of oligozoospermic men from infertile couples. DESIGN: A consecutive group of oligozoospermic men from infertile couples were offered bilateral testicular biopsy. The observed prevalence of carcinoma in situ was compared with the expected prevalence of testicular cancer in a corresponding age matched population of Danish men, assuming all untreated cases of carcinoma in situ progress to tumour stage. This calculation was based on data from the Danish Cancer Registry. SUBJECTS: 207 men aged 18-50 years who had sperm density below 10 million/ml in two samples within the previous 2 years or sperm density below 20 million/ml in two samples within the previous 2 years and a history of cryptorchidism or one or two atrophic testicles (orchidometer volume less than 15 cm3), or both. INTERVENTIONS: Bilateral testicular biopsies. MAIN OUTCOME MEASURES: Carcinoma in situ in the biopsy specimen. RESULTS: No case of carcinoma in situ was found among the 207 men. The expected number in a normal age matched population of corresponding size was 0.8. CONCLUSIONS: There is no increase in risk of carcinoma in situ of the testis in moderately oligozoospermic men of couples referred because of infertility.     

Levels of selenium in plasma and glutathione peroxidase in erythrocytes and the risk of breast cancer

Plasma selenium and glutathione peroxidase in erythrocytes were analyzed in a case-control study encompassing 441 cases with breast cancer and 191 controls with benign breast disease. No difference in mean serum selenium level between cases and controls on supplementary selenium intake was seen. If only individuals without supplementary intake, 278 cases and 135 controls, were considered a preventive effect was found increasing with selenium level. This finding was significant among women 50 years old or more with Mantel-Haenszel odds ratio=0.16 for individuals with serum selenium >1.21 μmol/L. Also for subjects with serum selenium in the range 1.00–1.21 μmol/L a significant preventive effect was seen with odds ratio=0.38. For women under 50 years of age a nonsignificant preventive effect was seen. Glutathione peroxidase in erythrocytes did not correlate well with serum selenium and was not a marker for the risk of breast cancer.     

Life history of the individuals buried in the St. Benedict Cemetery (Prague, 15th–18th Centuries): Insights from 14C dating and stable isotope (δ13C, δ15N, δ18O) analysis

Funerary practices and bioarchaeological (sex and age) data suggest that a mortality crisis linked to an epidemic episode occurred during the fifth phase of the St. Benedict cemetery in Prague (Czech Republic). To identify this mass mortality episode, we reconstructed individual life histories (dietary and mobility factors), assessed the population's biological homogeneity, and proposed a new chronology through stable isotope analysis (δ¹³C, δ¹⁸O and δ¹⁵N) and direct radiocarbon dating. Stable isotope analysis was conducted on the bone and tooth enamel (collagen and carbonate) of 19 individuals from three multiple graves (MG) and 12 individuals from individual graves (IG). The δ¹⁵N values of collagen and the difference between the δ¹³C values of collagen and bone carbonate could indicate that the IG individuals had a richer protein diet than the MG individuals or different food resources. The human bone and enamel carbonate and δ¹⁸O values suggest that the majority of individuals from MG and all individuals from IG spent most of their lives outside of the Bohemian region. Variations in δ¹⁸O values also indicate that all individuals experienced residential mobility during their lives. The stable isotope results, biological (age and sex) data and eight ¹⁴C dates clearly differentiate the MG and IG groups. The present work provides evidence for the reuse of the St. Benedict cemetery to bury soldiers despite the funeral protest ban (1635 AD). The Siege of Prague (1742 AD) by French‐Bavarian‐Saxon armies is identified as the cause of the St. Benedict mass mortality event. Am J Phys Anthropol 151:202–214, 2013. © 2013 Wiley Periodicals, Inc.     

Genetic analysis of breast cancer in the cancer and steroid hormone study.

The familial risk of breast cancer is investigated in a large population-based, case-control study conducted by the Centers for Disease Control. The data set is based on 4,730 histologically confirmed breast cancer cases aged 20 to 54 years and on 4,688 controls who were frequency matched to cases on the basis of both geographic region and 5-year categories of age, and it includes family histories, obtained through interviews of cases and controls, of breast cancer in mothers and sisters. Segregation analysis and goodness-of-fit tests of genetic models provide evidence for the existence of a rare autosomal dominant allele (q = .0033) leading to increased susceptibility to breast cancer. The effect of genotype on the risk of breast cancer is shown to be a function of a woman's age. Although, compared with noncarriers, carriers of the allele appear to be at greater risk at all ages, the ratio of age-specific risks is greatest at young ages and declines steadily thereafter. The proportion of cases predicted to carry the allele is highest (36%) among cases aged 20-29 years. This proportion gradually decreases to 1% among cases aged 80 years or older. The cumulative lifetime risk of breast cancer for women who carry the susceptibility allele is predicted to be high, approximately 92%, while the cumulative lifetime risk for noncarriers is estimated to be approximately 10%.     

Investigating causation in cancer clusters

Questions concerning clusters of cancer cases frequently arise in public health practice. The process of investigating any such cluster requires awareness that such case groupings can easily occur by chance and that any search for biologically meaningful causes will be severely constrained by various methodologic difficulties. These include (1) the long and probably variable latent periods between causative events and cancer diagnosis, (2) the limited numbers of cases available for study in any given cluster situation, and (3) the clinical non-specificity of cancer cases whereby no readily available means are at hand to identify the specific causes for any particular case. Evaluation of any given cluster should involve careful consideration of such limitations, together with a preliminary assessment of the specific cases involved and their community or workplace setting, before more intensive study is undertaken. Received: 22 February 1996 / Accepted in revised form: 13 June 1996     

Spatial Analysis of Childhood Cancer: A Case/Control Study

BackgroundChildhood cancer was the leading cause of death among children aged 1-14 years for 2012 in Spain. Leukemia has the highest incidence, followed by tumors of the central nervous system (CNS) and lymphomas (Hodgkin lymphoma, HL, and Non-Hodgkin’s lymphoma, NHL). Spatial distribution of childhood cancer cases has been under concern with the aim of identifying potential risk factors.ObjectiveThe two objectives are to study overall spatial clustering and cluster detection of cases of the three main childhood cancer causes, looking to increase etiological knowledge.MethodsWe ran a case-control study. The cases were children aged 0 to 14 diagnosed with leukemia, lymphomas (HL and NHL) or CNS neoplasm in five Spanish regions for the period 1996-2011. As a control group, we used a sample from the Birth Registry matching every case by year of birth, autonomous region of residence and sex with six controls. We geocoded and validated the address of the cases and controls. For our two objectives we used two different methodologies. For the first, for overall spatial clustering detection, we used the differences of K functions from the spatial point patterns perspective proposed by Diggle and Chetwynd and the second, for cluster detection, we used the spatial scan statistic proposed by Kulldorff with a level for statistical significance of 0.05.ResultsWe had 1062 cases of leukemia, 714 cases of CNS, 92 of HL and 246 of NHL. Accordingly we had 6 times the number of controls, 6372 controls for leukemia, 4284 controls for CNS, 552 controls for HL and 1476 controls for NHL. We found variations in the estimated empirical D(s) for the different regions and cancers, including some overall spatial clustering for specific regions and distances. We did not find statistically significant clusters.ConclusionsThe variations in the estimated empirical D(s) for the different regions and cancers could be partially explained by the differences in the spatial distribution of the population; however, according to the literature, we cannot discard environmental hazards or infections agents in the etiology of these cancers.     

What you are makes you eat different things-interrelations of diet,status, and sex in the early medieval population of Kirchheim unter Teck,FGR

Trace element data of the adult and immature individuals (n=151) from the early medieval graveyard at Kichheim unter Teck were subjected to cluster analysis. Distinct dietary groups resulted for both age categories that show differential access to animal protein. The assumption that these clusters represent social groups could generally be confirmed by comparison with archaeological data on status-indicating features. The distribution of individuals within the clusters was significantly different for the sexes, thus pointing to the detection of differential nutritional habits and behaviour categories by bone chemical analysis.     

A 30‐year Follow‐up of the Effects of Child Abuse and Neglect on Obesity in Adulthood

Childhood maltreatment has been implicated as a risk factor for adult obesity. We describe the first prospective assessment of adult obesity in individuals with documented histories of childhood physical and sexual abuse and neglect and a matched comparison group in a 30‐year follow‐up. Using a prospective cohort design, children with court substantiated cases of physical and sexual abuse and neglect (ages 0–11 years) from a Midwest county during 1967–1971 (n = 410) were matched with children without histories of abuse or neglect on age, sex, race/ethnicity and approximate family social class (n = 303) and followed up and assessed at mean age 41. Outcome measures include BMI and obesity assessed in 2003–2004 as part of a medical status examination and interview. Childhood physical abuse predicted significantly higher BMI scores in adulthood (β = 0.14, P < 0.05), even controlling for demographic characteristics, cigarette smoking, and alcohol consumption (β = 0.16, P < 0.01). Childhood sexual abuse (β = 0.07, not significant) and neglect (β = 0.02, not significant) were not significant predictors of adult BMI scores. These results demonstrate the long‐term impact of childhood physical abuse on weight into adulthood and suggest that physically abused children may be at risk for other adverse health outcomes associated with increased weight. Health professionals need to understand this risk for physically abused children and researchers should identify and evaluate strategies for effective interventions.