Excess Disease Risk Research Articles

Exposure to particulate matter and risk of amyotrophic lateral sclerosis: A case-control study in Northern Italy

Background: Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease with still unknown etiology. Role of occupational and environmental risk factors has been investigated, including outdoor air pollutants, which have been recently associated to an excess disease risk. We carried out a case-control study in order to assess if environmental exposure to particulate matter ≤10 µm (PM10) may increase ALS risk. Methods: We recruited patients referred to the Modena Neurology Unit between 1994-2015 and controls from the Modena province population. Using a validated geographical information system-based dispersion model, we geocoded subjects’ addresses of residence at the time of diagnosis and we estimated outdoor air PM10 concentrations for each subjects. We computed odds ratio (OR) and 95% confidence interval (CI) of ALS according to increasing PM10 exposure, using an unconditional logistic regression model age- and sex-adjusted. Results: For the 132 study participants (52 cases/80 controls), mean of annual average and maximum PM10 concentrations were 5.2 and 38.6µg/m3, respectively. Using fixed cutpoints at 5, 10 and 20 of average annual PM10 concentrations, compared with subjects <5µg/m3, we did not find evidence for an excess ALS risk associated with PM10 exposure, since OR was 0.87 (95% CI 0.39-1.96), 0.94 (0.24-3.70), and 0.87 (0.05-15.01) at 5-10, 10-20 and ≥20µg/m3, respectively. Using maximum annual PM10 concentrations, we found an excess ALS risk for subjects exposed at 10-20µg/m3 (OR=4.27, 0.69-26.51) compared with exposure below 10µg/m3, although the risk tended to decrease at higher PM10 concentrations, with OR of 1.49 (0.39-5.75) at 20-50, and 1.16 (0.98-4.82) at ≥50µg/m3. Conclusions: Our findings do not suggest that PM10 exposure is associated with ALS risk. However, some evidence of an increased risk associated with maximum annual exposure concentrations, although statistically imprecise, suggests the need of further investigations, also considering the high concentrations of particulate matter characterizing Northern Italy.

Population-Attributable Risk for Cardiovascular Disease Associated With Hypertension in Black Adults

The prevalence of hypertension and the risk for hypertension-related cardiovascular disease (CVD) are high among black adults. The population-attributable risk (PAR) accounts for both prevalence and excess risk of disease associated with a risk factor. To examine the PAR for CVD associated with hypertension among black adults. This prospective cohort study used data on 12 497 black participants older than 21 years without CVD at baseline who were enrolled in the Jackson Heart Study (JHS) from September 26, 2000, through March 31, 2004, and cardiovascular events were adjudicated through December 31, 2015. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants were enrolled from July 1, 2003, through September 12, 2007, and cardiovascular events were adjudicated through March 31, 2016. Data analysis was performed from March 26, 2018, through July 10, 2019. Normal blood pressure and hypertension were defined using the 2017 American College of Cardiology/American Heart Association blood pressure guideline thresholds. The PAR for CVD associated with hypertension, calculated using multivariable-adjusted hazard ratios (HRs) for CVD, coronary heart disease, heart failure, and stroke associated with hypertension vs normal blood pressure. Prevalence of hypertension among non-Hispanic black US adults 21 years and older without CVD was calculated using data from the National Health and Nutrition Examination Survey, 2011-2014. Of 12 497 participants, 1935 had normal blood pressure (638 [33.0%] male; mean [SD] age, 53.5 [12.4] years), 929 had elevated blood pressure (382 [41.1%] male; mean [SD] age, 58.6 [11.8] years), and 9633 had hypertension (3492 [36.3%] male; mean [SD] age, 62.0 [10.3] years). For a maximum 14.3 years of follow-up, 1235 JHS and REGARDS study participants (9.9%) experienced a CVD event. The multivariable-adjusted HR associated with hypertension was 1.91 (95% CI, 1.48-2.46) for CVD, 2.41 (95% CI, 1.59-3.66) for coronary heart disease, 1.52 (95% CI, 1.01-2.30) for heart failure, and 2.20 (95% CI, 1.44-3.36) for stroke. The prevalence of hypertension was 53.2% among non-Hispanic black individuals. The PAR associated with hypertension was 32.5% (95% CI, 20.5%-43.6%) for CVD, 42.7% (95% CI, 24.0%-58.4%) for coronary heart disease, 21.6% (95% CI, 0.6%-40.8%) for heart failure, and 38.9% (95% CI, 19.4%-55.6%) for stroke. The PAR was higher among those younger than 60 years (54.6% [95% CI, 37.2%-68.7%]) compared with those 60 years or older (32.0% [95% CI, 11.9%-48.1%]). No differences were present in subgroup analyses. These findings suggest that a substantial proportion of CVD cases among black individuals are associated with hypertension. Interventions to maintain normal blood pressure throughout the life course may reduce the incidence of CVD in this population.

High mortality due to congenital malformations in children aged

BackgroundIn French Guiana, pregnant women may be exposed to infectious, environmental, and social risks leading to congenital malformation. The objective of the study was to study mortality rates from congenital malformations among infants < 1 year and to compare them with those in mainland France.MethodsWe used the CEPI DC (INSERM) database, which compiles annual data from death certificates in all French territories using the International Classification of Diseases. Annual deaths for French Guiana and mainland France between 2005 and 2015 were compiled. The age category studied was children less than 1 year and deaths from congenital malformations, deformations and chromosomal abnormalities were compiled. Crude risk ratios and 95% confidence intervals were calculated to quantify the excess risk of disease in French Guiana.ResultsIn French Guiana between 2005 and 2015 there were 666 deaths of children aged < 1 year, among which, 132 (19.8%) were due to congenital malformations and chromosomal anomalies. Overall the risk ratio of death from congenital malformations and chromosomal anomalies between French Guiana and mainland France was 2.7 (1.5–4.7), P < 0.001 for neurological congenital malformations it was 4.8 (1.2–19.7), P = 0.01 and for congenital malformations of the circulatory system it was 3.3 (1.5–6.9), P = 0.001.ConclusionsThe incidence of death from congenital malformations or chromosomal anomalies in French Guiana was significantly higher than in mainland France. Explanations for this may be infections, genetic causes, nutritional causes, and toxic causes that are prevalent. There is a need to identify factors that predispose children born in French Guiana to having a higher risk of congenital malformations and chromosomal anomalies.

A case-control study of the risk of cutaneous melanoma associated with three selenium exposure indicators

A direct association between exposure to the metalloid selenium and risk of cutaneous melanoma has been suggested by some observational and experimental cohort studies, whereas other studies have yielded inconsistent results. Since some of the inconsistencies may be due to exposure misclassification arising from the use of exposure indicators that do not adequately reflect body tissue selenium content or the levels of the biologically relevant species of this metalloid, we examined this issue using multiple indicators of exposure. We analyzed the relation of selenium exposure with risk of cutaneous melanoma using two different biomarkers, plasma and toenail selenium concentration, and estimated dietary selenium intake in a population-based case-control series (54 cases, 56 controls) from an Italian community. In unmatched and matched logistic regression models as well as nonparametric generalized additive models, higher plasma selenium levels were strongly associated with excess disease risk. In contrast, toenail and dietary selenium exhibited little relation with melanoma risk. The pattern of correlation among indicators of exposure differed by disease status, with dietary intake associated with plasma selenium levels in patients but not in controls. Our data showed that different selenium exposure indicators can yield different inferences about melanoma risk. Although the series was small, our results are consistent with a positive association between circulating levels of selenium and melanoma risk. Further investigation of the exposure classification performance of various selenium biomarkers and of metabolic patterns of the metalloid and of its speciation are needed to help elucidate the relation between selenium exposure and human health.

Magnetic fields exposure from high-voltage power lines and risk of amyotrophic lateral sclerosis in two Italian populations

The aetiology of amyotrophic lateral sclerosis (ALS), a rare and extremely severe neurodegenerative disease, has been associated with magnetic fields exposure. However, evidence for such a relation in the general population is weak, although the previous null results might also be due to exposure misclassification, or a relationship might exist only for selected subgroups. To test such a hypothesis we carried out a population-based case-control study in two Northern and Southern Italy regions, including 703 ALS cases newly diagnosed from 1998 to 2011 and 2737 controls randomly selected from the residents in the study provinces. Overall, we found that a residence near high-voltage power lines, within the corridors yielding a magnetic fields of ≥0.1 μT, was not associated with an excess disease risk, nor did we identify a dose-response relationship after splitting the exposed corridor according to the 0.1, 0.2 and 0.4 μT cut-points of exposure. These results were confirmed taking into account age at onset, period of diagnosis, sex, geographical area, and length of exposure. Overall, despite the residual possibility of unmeasured confounding or small susceptible subgroups not identified in our study, these results appear to confirm that the exposure to magnetic fields from power lines occurring in the general population is not associated with increased ALS risk.

Coronary Artery Calcium in Early Midlife Is Associated with Excess Coronary Heart Disease Risk

Coronary artery calcium (CAC) is a strong predictor of adverse coronary heart disease (CHD) events in older adults. In this study, researchers

Abstract 1776: Aspirin use among African American men reduces prostate cancer risk: Findings from the NCI-Maryland Prostate Cancer Case-Control study

Abstract Prostate cancer is a leading cause of cancer death in US men. Yet, the etiology of prostate cancer remains poorly understood, with only older age, African ancestry, family history of the disease, and multiple germline genetic variations being established disease risk factors. Prostate cancer occurs more often in African-American men and Caribbean men of African descent than in men of other race/ethnicities. The causes of these racial and ethnic differences are multifactorial, but it has been proposed that differences in tumor biology contribute to the health disparity associated with prostate cancer. Previously, our laboratory discovered immunobiology differences between African-American and European-American men where genes involved in the inflammatory response tended to be up-regulated in tumors of African American patients. Accumulating evidence suggests that inflammation may be involved in prostate carcinogenesis. Given these observations, we hypothesized that inflammation may contribute to prostate cancer risk and the survival health disparity observed between African-Americans and European-Americans. To this end, we conducted a case-control study in the greater Baltimore area where we recruited 1000 cases and 1000 controls composed of equal populations of African-American and European-American men. In our survey, we asked about non-steroidal anti-inflammatory drugs (NSAIDs) use categorized into aspirin, Tylenol, and other pain relievers that neither contain Tylenol nor aspirin. We found a significant association between aspirin use and prostate cancer risk—where aspirin use decreased the risk of prostate cancer. Strikingly, the decreased prostate cancer risk as a result of aspirin use was most profound in African-American men. We were also able to measure the levels of C-reactive protein, a marker for inflammation, to further evaluate the relationship between aspirin use, inflammation, and prostate cancer risk. Indeed, we did observe a decrease in C-reactive protein in patients who took aspirin. Interestingly, overall levels in healthy controls and prostate cases were higher in African-American subjects and patients when compared to European-Americans. Although aspirin use decreased C-reactive protein levels in African-American and European-American cases, African-Americans had significantly higher levels of C-reactive protein. The robust association between aspirin consumption and prostate cancer risk suggests that inflammation might be a driver in prostate cancer of African-American men. Additionally, the increased levels of C-reactive protein in African-American controls and cases might contribute to the excessive disease risk and mortality among these men. Citation Format: Cheryl J. Smith, Symone Jordan, Tiffany H. Dorsey, Dean Mann, Chris A. Loffredo, Elise Bowman, Wei Tang, Stefan Ambs. Aspirin use among African American men reduces prostate cancer risk: Findings from the NCI-Maryland Prostate Cancer Case-Control study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1776.

Prevalence, incidence and concomitant co-morbidities of type 2 diabetes mellitus in South Western Germany--a retrospective cohort and case control study in claims data of a large statutory health insurance.

BackgroundType 2 diabetes mellitus (T2DM) has become a world-wide epidemic. This chronic metabolic disease has a major impact on life expectancy and on quality of life. The burden of this disease includes a number of co-morbidities. However, estimates of prevalence, incidence and associated diseases as well as the current temporal development and regional differences are largely missing for South Western Germany.MethodsLifetime diagnosis-based prevalence, incidence and presence of concomitant co-morbidities were examined between the years 2007 and 2010 in the claims data set of all insured persons of the AOK Baden-Wuerttemberg, a large statutory health insurance. The analysis was based on the respective WHO-ICD-10 codes. Data were standardized for age and sex on the residential population of about 10 million inhabitants of South Western Germany.ResultsThe total study cohort involved approximately 3.5 million persons each year. The standardized diagnosis-based prevalence (SDP) of T2DM rose from 6.6 %, 7.4 %, 8.0 %, up to 8.6 % in the years 2007 to 2010. Yearly SDP was between 14.0 % and 18.9 % at an age range of 60 to 64 years and between 26.7 % and 31.8 % at an age of 75 years or older. In the year 2010 the regional distributions of standardized diagnosis-based prevalence were between 7.6 % and 11.6 %, respectively. Incidence rates were 8.3 in 2008, 7.8 in 2009, and 8.7 in 2010 (all rates per 1000). The excess disease risk (odds ratio) of T2DM was for adiposity 2.8 to 3.0, hypertension 2.4 to 3.7, coronary heart disease 1.8 to 1.9, stroke 1.7 to 1.8, renal insufficiency 2.8 to 3.4, and retinopathy 2.8 to 2.9 in the years 2007 to 2010. These co-morbidities appeared several years earlier compared to the non-diabetic population.ConclusionsT2DM is common and increasing in South Western Germany. In particular a quarter of the population in higher ages was afflicted by T2DM. Interestingly a region-specific pattern was observed as well as an increase in numbers during earlier years in life. Our data underline the need for diabetes awareness programmes including early diagnosis measures as well as structured and timely health surveys for major diseases such as T2DM and its concomitant co-morbidities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12889-015-2188-1) contains supplementary material, which is available to authorized users.

A Case-Control Study of the Risk of Cutaneous Melanoma Associated with Three Selenium Exposure Indicators

A direct association between exposure to the metalloid selenium and risk of cutaneous melanoma has been suggested by some observational and experimental cohort studies, whereas other studies have yielded inconsistent results. Since some of the inconsistencies may be due to exposure misclassification arising from the use of exposure indicators that do not adequately reflect body tissue selenium content or the levels of the biologically relevant species of this metalloid, we examined this issue using multiple indicators of exposure. We analyzed the relation of selenium exposure with risk of cutaneous melanoma using two different biomarkers, plasma and toenail selenium concentration, and estimated dietary selenium intake in a population-based case-control series (54 cases, 56 controls) from an Italian community. In unmatched and matched logistic regression models as well as nonparametric generalized additive models, higher plasma selenium levels were strongly associated with excess disease risk. In contrast, toenail and dietary selenium exhibited little relation with melanoma risk. The pattern of correlation among indicators of exposure differed by disease status, with dietary intake associated with plasma selenium levels in patients but not in controls. Our data showed that different selenium exposure indicators can yield different inferences about melanoma risk. Although the series was small, our results are consistent with a positive association between circulating levels of selenium and melanoma risk. Further investigation of the exposure classification performance of various selenium biomarkers and of metabolic patterns of the metalloid and of its speciation are needed to help elucidate the relation between selenium exposure and human health.

Latency Models for Analyses of Protracted Exposures

The effect of an increment of exposure on disease risk may vary with time-since-exposure. If the pattern of temporal variation is simple (eg, a peak and then a decline in excess risk of disease) then this may be modeled efficiently via a parametric latency function. Estimation of the parameters for such a model can be difficult because the parameters are not a function of a simple summary of the exposure history. Typically, such parameters are estimated via an iterative search that requires calculating a different time-weighted exposure for each combination of the latency function parameters. This article describes a simple approach to fitting logistic regression models that include a parametric latency function. This approach is illustrated using data from a study of the association between radon exposure and lung cancer mortality among underground uranium miners. This approach should facilitate fitting models to assess variation with time since exposure in the effect of a protracted environmental or occupational exposure.

Estimation of the impact on children’s health of environmental tobacco smoke in England and Wales

In this paper, the population attributable risk (PAR), a measure of the excess risk of disease associated with a risk factor, is calculated for some of the common adverse health effects that have been associated with exposure of children to environmental tobacco smoke (ETS): childhood lower respiratory illness, chronic middle ear disease, asthma and sudden infant death syndrome (SIDS). Published data on both risk estimates and the percentage of children exposed to ETS in the home (prevalence of ETS) have been utilised. The percentage of childhood lower respiratory illness and middle ear disease typically attributable to ETS from either parent smoking ranged from 9% for asthma prevalence and for referral for glue ear, to 25% for hospital admission for lower respiratory illness. Where data were available to calculate PARs separately for mother only smoking and father only smoking, the PARs were generally larger for mothers only smoking, due mainly to higher odds ratios for mothers only smoking. The PAR for SIDS attributable to ETS from mother only smoking was 11%. Although based on a small number of studies, the PAR for SIDS attributable to smoking of fathers only was similar to that attributable to the smoking of mothers only, largely due to the higher prevalence of households where only the father smokes. This study has shown that the impact of ETS on childhood illness can be considerable, emphasising the importance of the need to develop effective strategies for reducing the risk of ETS exposure in the home and elsewhere.

Attributable fractions: fundamental concepts and their visualization.

A general methodology for visualizing attributable fractions in epidemiology is described. The methodology applies to the multifactorial exposure situation and embraces various types of attributable fractions including adjusted, sequential and average attributable fractions. The concept of the scaled Venn diagram plays a central role, illustrating total disease risk and excess disease risk attributable to the exposures as areas in a unit square. This forms the ground for making simple pie charts of attributable fractions summing to 1 (or 100%). The potential applications extend from cohort and cross-sectional data to data from case-control studies. The methodology is illustrated by theoretical as well as empirical examples including the risk of motor fatalities attributable to driver's blood alcohol concentration and age, and the prevalence of chronic cough attributable to smoking habits, occupational exposure to dust or gas, and residence. A total of 40 figures illustrate the methodology.

Risks of Occupational Respiratory Diseases among U.S. Coal Miners

Abstract The excess (exposure-attributable) risks of certain respiratory diseases and outcomes were estimated for U.S. coal miners exposed to respirable coal mine dust for various durations and concentrations, including a 45-year working lifetime at the current 2-mg/m3 standard. Multiple linear and logistic regression models were used to compute predicted prevalence and excess risk of disease, using data and regression results from published epidemiological studies of U.S. coal miners. Disease outcomes evaluated include simple coal workers' pneumoconiosis, progressive massive fibrosis, and clinically significant deficits in lung function, measured as forced expiratory volume in 1 second of < 80% or < 65% of predicted normal values. Point estimates of excess risk of progressive massive fibrosis ranged from 1/1000 to 167/1000 among coal miners exposed to respirable coal mine dust at a mean concentration of 2 mg/m3 for 45 years. This range reflects coal rank and study differences. Point estimates for an exce...

Prevalence of thyroid antibodies among healthy middle-aged women: Findings from the thyroid study in healthy women

Autoimmune thyroiditis is the most common cause of subclinical hypothyroidism in North America, is more common in women than men, and is a risk factor for the development of coronary heart disease (CHD). We measured thyroid-stimulating hormone (TSH) and two thyroid antibodies, thyroid peroxidase and thyroglobulin, in stored sera of the participants (aged 44 to 54 years) of the Healthy Women Study. We selected 254 samples from the premenopausal baseline examination in 1983 to 1985 and from a follow-up examination that occurred an average of 5.7 years later (range, 3 to 7.7 years). At follow-up, 95 women remained premenopausal, 98 had ceased menstruating for at least 12 months, and 61 were taking postmenopausal hormone therapy. Overall, the prevalence of the thyroid antibodies in this healthy population was high at both time points (21 to 26%). Women with antibodies had higher TSH concentrations than did those with no antibodies (2.68 ± 1.3 versus 1.51 ± 73 mU/L, P < 0.001); this relationship was statistically significant even after excluding those with subclinical hypothyroidism (TSH > 6.0 mU/L). TSH and antibody levels did not differ by menopausal status or hormone therapy use at follow-up. Given the high prevalence of thyroid antibodies among healthy middle-aged women, long-term follow-up is warranted to ascertain whether the presence of antibodies is associated with subsequent excess risk of disease, in particular, CHD.

Elevated antibody titers to Epstein-Barr virus prior to the diagnosis of Epstein-Barr-virus-associated gastric adenocarcinoma.

Epstein-Barr virus (EBV) has recently been identified in the tumor cells of patients with gastric carcinoma. We tested pre-morbid serum samples from a carefully monitored cohort of Japanese men in order to investigate the possibility that patients with EBV-associated gastric cancer represent a sub-set of individuals with long-standing difficulties in appropriately managing EBV infection. From a serum bank, we obtained 108 samples derived from 54 patients destined to develop gastric adenocarcinoma and 54 controls. Samples were tested under code for antibodies to EBV-capsid antigen, early antigen and nuclear antigen. Individuals who were positive for IgA antibodies against EBV viral-capsid antigen (VCA) and IgG antibodies against the R component of EBV early antigen were at a 3.9-fold and 1.9-fold excess risk of disease, respectively. Antibody titers to EBV VCA were significantly higher in those destined to get EBV-associated gastric cancer than those subsequently developing non-EBV-associated gastric cancer or age-and-gender-matched controls. These findings suggest that the inability to control EBV infection on a long-term basis exists many years prior to the development of EBV-associated gastric cancer, and that EBV may play an etiologic role in this sub-set of malignancies.

Familial aggregation of cardiovascular diseases in African-American pedigrees.

Familial aggregation of cardiovascular diseases and diabetes has been consistently demonstrated. However, virtually all of the evidence on the familial patterns of these diseases has come from white population samples. This study evaluates the level of familial excess risk among first degree relatives of 232 African-American pedigrees which included 1,420 individuals recruited from the Chicago, IL, area. Excess disease risk was observed among relatives (parents and offsprings) of affected probands compared to relatives of unaffected probands for coronary heart disease (odds ratio [OR] = 5.30; 95% confidence interval [CI] = 2.51-11.23); hypertension (OR = 1.98; CI = 1.41-2.80); stroke (OR = 3.24; CI = 1.08-9.70); and diabetes (OR = 2.95; CI = 1.55-5.62). The results of this study clearly show that coronary heart disease, hypertension, stroke, and diabetes aggregate in some African-American families and not others. Unaffected relatives of persons suffering from these diseases should be encouraged to have their blood pressure, lipid, and blood glucose levels measured at frequent intervals. These recommendations are particularly urgent in African-American communities because of the disproportionately high morbidity and mortality experienced from cardiovascular diseases and diabetes.

Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: results from a case-control study.

In a case-control study of NPC conducted in the Philippines, 104 predominantly non-Chinese (< 10% ethnically Chinese) cases of nasopharyngeal carcinoma (NPC) and 205 hospital and community controls were recruited. Risk factor information was obtained through personal interview. The occupational history of each subject was reviewed "blind" by an industrial hygienist to determine estimates of exposure to formaldehyde, solvents, dusts, exhaust and pesticides. After control for confounding, subjects who were first exposed to formaldehyde 25 or more years prior to diagnosis/interview or wo were first exposed before the age of 25 were found, in relation to those never exposed, to be at a 4.0-fold excess risk of disease. Similarly, those first exposed to dust and/or exhaust 35 or more years prior to diagnosis/interview were at a 4.4-fold excess risk of disease and those first exposed before the age of 20 were at a 3.5-fold excess risk of disease. Salted fish consumption was not associated with risk, while consumption of processed meats protected against NPC. Smoking was positively associated with NPC, but only when cases were compared to community controls. Relative to non-smokers, subjects reporting more than 30 years of smoking were at an adjusted 7.2-fold excess risk of disease. Herbal medicine use and burning of anti-mosquito coils were both independently associated with risk of NPC, with ever-users of herbal medicines being at a 2.5-fold excess risk of disease and those reporting daily use of anti-mosquito coils being at a 5.9-fold excess risk of disease relative to never users. Exposure to solvents, pesticides, or use of betel nuts were not associated with NPC risk.

Detection of excess disease risk in family data: Response to Lubin and Bale

Detection of excess disease risk in family data: Response to Lubin and Bale

On the detection of excess disease risk in family data.

On the detection of excess disease risk in family data.

A method to detect excess risk of disease in structured data: cancer in relatives of retinoblastoma patients.

It is often of interest to know whether there is increased occurrence of a trait in a pedigree or other structured set of epidemiological data. In answering such questions most current methods use aggregate measures, such as relative risk, that may not relate the outcome for each individual to that individual's risk. In this paper we present a simple method, and its computational algorithm, to overcome this limitation. This new method also permits one to identify high-risk families or subsets of a collection of data, which is not always possible using other approaches. In a study of cancer risk among relatives of retinoblastoma patients, by applying this new method it was found that 11 of 33 families each obtained through a unilateral retinoblastoma patient are at statistically high risk of cancer at all sites combined, while there are 15 of 47 such families obtained through a bilaterally affected proband. These results are unlikely to have occurred by chance, indicating an overall excess risk in the ancestors of these retinoblastoma cases. The proposed test procedure does not specify the cause of elevated risk; however, a method is proposed that provides some indication regarding possible causal mechanisms under some circumstances.