Noel S. Weiss

A Case–Control Study of Screening Sigmoidoscopy and Mortality from Colorectal Cancer

BACKGROUND The efficacy of sigmoidoscopic screening in reducing mortality from colorectal cancer remains uncertain. A randomized trial would be ideal for clarifying this issue but is very difficult to conduct. Case-control studies provide an alternative method of estimating the efficacy of screening sigmoidoscopy. METHODS Using data on the 261 members of the Kaiser Permanente Medical Care Program who died of cancer of the rectum or distal colon from 1971 to 1988, we examined the use of screening by rigid sigmoidoscopy during the 10 years before the diagnosis and compared it with the use of screening in 868 control subjects matched with the case subjects for age and sex. RESULTS Only 8.8 percent of the case subjects had undergone screening by sigmoidoscopy, as compared with 24.2 percent of the controls (matched odds ratio, 0.30; 95 percent confidence interval, 0.19 to 0.48). Adjustment for potential confounding factors increased the odds ratio to 0.41 (95 percent confidence interval, 0.25 to 0.69). The negative association was as strong when the most recent sigmoidoscopy was 9 to 10 years before diagnosis as it was when examinations were more recent. By contrast, for 268 subjects with fatal colon cancer above the reach of the sigmoidoscope and for 268 controls, the adjusted odds ratio was 0.96 (95 percent confidence interval, 0.61 to 1.50). The specificity of the negative association for cancer within the reach of the sigmoidoscope is consistent with a true efficacy of screening rather than a confounding by unmeasured selection factors. CONCLUSIONS Screening by sigmoidoscopy can reduce mortality from cancer of the rectum and distal colon. A screening once every 10 years may be nearly as efficacious as more frequent screening.

Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen.

We interviewed 327 women who had been 50 to 74 years of age when treated for fracture of the hip of lower forearm, to determine their use (or lack of use) of estrogen preparations. Their responses were compared with those in a random sample of 567 women who were of similar age and from the same region. The risk of fracture was 50 to 60 per cent lower in women who had used these drugs for six years or longer than in women who hadnot used them (95 per cent confidence interval of relative risk, 0.3 to 0.6); those using them for shorter periods received less benefit, if any. A decreased risk of fracture was clearly evident only in women still taking estrogens and evident at either common daily dose (0.625 and 1.25 mg). In conjunction with the finding that estrogens can retard the development of osteoporosis in postmenopausal women, our data argue that lowering of the risk of hip and forearm fractures must be weighed as a benefit of long-term estrogen use.

Ovarian Tumors in a Cohort of Infertile Women

BACKGROUND Case reports and the results of a recent case-control study have raised questions about the potential neoplastic effects of medications used as treatment for infertility. METHODS We examined the risk of ovarian tumors in a cohort of 3837 women evaluated for infertility between 1974 and 1985 in Seattle. Computer linkage with a population-based tumor registry was used to identify women in whom tumors were diagnosed before January 1, 1992. Data on infertility testing and treatment were abstracted from the medical records of women who had ovarian cancer and those of a randomly selected comparison group. The risk of ovarian tumors associated with exposure to ovulation-inducing medications was assessed through an age-standardized comparison with the rate of ovarian tumors in the general population, and Cox regression analysis was used to compare the risk of cancer among women who received these medications with the risk among infertile women who did not receive them. RESULTS There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.4 (standardized incidence ratio, 2.5; 95 percent confidence interval, 1.3 to 4.5). Nine of the women in whom ovarian tumors developed had taken clomiphene; the adjusted relative risk among these women, as compared with that among infertile women who had not taken this drug, was 2.3 (95 percent confidence interval, 0.5 to 11.4). Five of the nine women had taken the drug during 12 or more monthly cycles. This period of treatment was associated with an increased risk of ovarian tumors among both women with ovarian abnormalities and those without apparent abnormalities (relative risk, 11.1; 95 percent confidence interval, 1.5 to 82.3), whereas treatment with the drug for less than one year was not associated with an increased risk. CONCLUSIONS Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.

Sexual Practices, Sexually Transmitted Diseases, and the Incidence of Anal Cancer

Abstract To elucidate the risk factors for anal cancer, we interviewed and obtained blood specimens from 148 persons with anal cancer and from 166 controls with colon cancer in whom these diseases were diagnosed during 1978–1985. We found that in men, a history of receptive anal intercourse (related to homosexual behavior) was strongly associated with the occurrence of anal cancer (relative risk, 33.1; 95 percent confidence interval, 4.0 to 272.1). Anal intercourse was only weakly associated with the risk of anal cancer in women (relative risk, 1.8; 95 percent confidence interval, 0.7 to 4.2). Among the subjects with squamous-cell anal cancer, 47.1 percent of homosexual men, 28.6 percent of heterosexual men, and 28.3 percent of women gave a history of genital warts, as compared with only 1 to 2 percent of controls and no patients with transitional-cell anal cancer. In patients without a history of warts, anal cancer was associated with a history of gonorrhea in heterosexual men (relative risk, 17.2; 95 pe...

Temporal trends in the prevalence of diabetic kidney disease in the United States

CONTEXT Diabetes is the leading cause of kidney disease in the developed world. Over time, the prevalence of diabetic kidney disease (DKD) may increase due to the expanding size of the diabetes population or decrease due to the implementation of diabetes therapies. OBJECTIVE To define temporal changes in DKD prevalence in the United States. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional analyses of the Third National Health and Nutrition Examination Survey (NHANES III) from 1988-1994 (N = 15,073), NHANES 1999-2004 (N = 13,045), and NHANES 2005-2008 (N = 9588). Participants with diabetes were defined by levels of hemoglobin A(1c) of 6.5% or greater, use of glucose-lowering medications, or both (n = 1431 in NHANES III; n = 1443 in NHANES 1999-2004; n = 1280 in NHANES 2005-2008). MAIN OUTCOME MEASURES Diabetic kidney disease was defined as diabetes with albuminuria (ratio of urine albumin to creatinine ≥30 mg/g), impaired glomerular filtration rate (<60 mL/min/1.73 m(2) estimated using the Chronic Kidney Disease Epidemiology Collaboration formula), or both. Prevalence of albuminuria was adjusted to estimate persistent albuminuria. RESULTS The prevalence of DKD in the US population was 2.2% (95% confidence interval [CI], 1.8%-2.6%) in NHANES III, 2.8% (95% CI, 2.4%-3.1%) in NHANES 1999-2004, and 3.3% (95% CI, 2.8%-3.7%) in NHANES 2005-2008 (P <.001 for trend). The prevalence of DKD increased in direct proportion to the prevalence of diabetes, without a change in the prevalence of DKD among those with diabetes. Among persons with diabetes, use of glucose-lowering medications increased from 56.2% (95% CI, 52.1%-60.4%) in NHANES III to 74.2% (95% CI, 70.4%-78.0%) in NHANES 2005-2008 (P <.001); use of renin-angiotensin-aldosterone system inhibitors increased from 11.2% (95% CI, 9.0%-13.4%) to 40.6% (95% CI, 37.2%-43.9%), respectively (P <.001); the prevalence of impaired glomerular filtration rate increased from 14.9% (95% CI, 12.1%-17.8%) to 17.7% (95% CI, 15.2%-20.2%), respectively (P = .03); and the prevalence of albuminuria decreased from 27.3% (95% CI, 22.0%-32.7%) to 23.7% (95% CI, 19.3%-28.0%), respectively, but this was not statistically significant (P = .07). CONCLUSIONS Prevalence of DKD in the United States increased from 1988 to 2008 in proportion to the prevalence of diabetes. Among persons with diabetes, prevalence of DKD was stable despite increased use of glucose-lowering medications and renin-angiotensin-aldosterone system inhibitors.

Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women

BACKGROUND Postmenopausal oestrogen therapy reduces the risk of osteoporosis and cardiovascular diseases but is associated with an increased risk of endometrial cancer. We have assessed the impact of a regimen of oestrogen with cyclic progestagen on risk of endometrial cancer for postmenopausal women. METHODS We did a population-based case-control study of women aged 45-74 years in western Washington State, USA. Cases were identified from a regional cancer registry as having histologically confirmed endometrial cancer during 1985-91. 832 (72%) of 1154 eligible cases completed interviews. Controls were identified by random digit dialling, screened for intact uterus, frequency matched for age and county, and randomly assigned a reference date within 1985-91. Interviews with 1114 (73%) of 1526 eligible controls were done. The women provided information about use of hormone replacement therapy, and reproductive and medical history before diagnosis date (cases) or reference date (controls). FINDINGS Relative to women who had never used hormones (for > 6 months), women who had taken unopposed oestrogen had a four-fold increase (95% CI 3.1-5.1) in risk of endometrial cancer. Women who used a combined therapy of oestrogen with cyclic progestagen (eg. medroxyprogesterone acetate) had a relative risk of 14 (1.0-1.9). Among women with fewer than 10 days of added progestagen per month, the relative risk was 3.1 (1.7-5.7). Whereas that for women with 10-21 days of added progestagen was 1.3 (0.8-2.2). The use of these combined regimens for 5 or more years was associated with risks of 3.7 (1.7-8.2) and 2.5 (1.1-5.5), respectively, relative to non-users of hormones. INTERPRETATION Postmenopausal women who use combined therapy of oestrogen with cyclic progestagen on a long-term basis have an increased risk of endometrial cancer compared with those who are not on hormone replacement, even when progestagen is added for 10 or more days per month. This increase is much smaller than that associated with unopposed oestrogen, but needs to be confirmed.

Incidence of Suicide in Persons With Cancer

PURPOSE The purpose of this study was to characterize suicide rates among patients with cancer in the United States and identify patient and disease characteristics associated with higher suicide rates. Prior studies, mostly in Europe, have suggested that patients with cancer may be at increased risk for suicide, but large cohort studies comparing patients with cancer with the general population have not been performed in the United States. METHODS Patients in the study were residents of geographic areas served by the Surveillance, Epidemiology, and End Results (SEER) program who were diagnosed with cancer from 1973 to 2002. Comparisons with the general US population were based on mortality data collected by the National Center for Health Statistics. This was a retrospective cohort study of suicide in persons with cancer. RESULTS Among 3,594,750 SEER registry patients observed for 18,604,308 person-years, 5,838 suicides were identified, for an age-, sex-, and race-adjusted rate of 31.4/100,000 person-years. In contrast, the suicide rate in the general US population was 16.7/100,000 person-years. Higher suicide rates were associated with male sex, white race, and older age at diagnosis. The highest suicide risks were observed in patients with cancers of the lung and bronchus (standardized mortality ratio [SMR] = 5.74; 95% CI, 5.30 to 6.22), stomach (SMR = 4.68; 95% CI, 3.81 to 5.70), oral cavity and pharynx (SMR = 3.66; 95% CI, 3.16 to 4.22), and larynx (SMR = 2.83; 95% CI, 2.31 to 3.44). SMRs were highest in the first 5 years after diagnosis with cancer. CONCLUSION Patients with cancer in the United States have nearly twice the incidence of suicide of the general population, and suicide rates vary among patients with cancers of different anatomic sites. Further examination of the psychological experience of patients with cancer, particularly that of patients with certain types of cancer, is warranted.

Insulin-like Growth Factors, Their Binding Proteins, and Prostate Cancer Risk: Analysis of Individual Patient Data from 12 Prospective Studies

Context Insulin-like growth factors (IGFs) and IGF binding proteins may be associated with some cancers. Contribution This reanalysis of individual patient data from 12 studies of the association between IGFs and IGF binding proteins and prostate cancer suggests that higher levels of serum IGF-I are associated with higher risk for prostate cancer. Caution The 12 studies varied in the types of patients they studied and in how they measured IGFs. Implication High IGF-I levels seem to be a risk factor for prostate cancer. The Editors Prostate cancer is one of the most common types of cancer in men, yet few risk factors for the disease, other than age, race, and a family history, have been established (1, 2). Insulin-like growth factors (IGFs) and their associated binding proteins (IGFBPs) have been the subject of many epidemiologic investigations of prostate cancer because they are known to help regulate cell proliferation, differentiation, and apoptosis (3). Although results from some, but not all, studies suggest an association between IGFs and IGFBPs and prostate cancer risk, there has been much uncertainty about its consistency and magnitude. A previous meta-analysis that included only 3 prospective studies suggested that high levels could be associated with more than a 2-fold increase in risk (4), although recent studies have suggested the risk is lower. Furthermore, given that these peptides are correlated with each other, uncertainty remains about any observed relationships. The individual studies are rarely large enough to allow proper mutual adjustment for these correlated factors, and they are insufficiently powered to investigate the consistency of their findings in key subgroups (for example, stage and grade of disease). Such analyses are important because studies have suggested that IGF-I might be more associated with advanced than with localized disease (5, 6). The Endogenous Hormones and Prostate Cancer Collaborative Group was established to conduct collaborative reanalyses of individual data from prospective studies on the relationships between circulating levels of sex hormones and IGFs and subsequent prostate cancer risk. Results for the sex hormones have been reported elsewhere and show no statistically significant relation between androgen or estrogen levels in men and the subsequent risk for prostate cancer (7). We report results for concentrations of IGFs and IGFBPs. Methods Participants The Endogenous Hormones and Prostate Cancer Collaborative Group is described in detail elsewhere (7). In brief, the group invited principal investigators of all studies, found by searching PubMed, Web of Science, and CancerLit, that provided data on circulating concentrations of sex steroids, IGFs or IGFBPs, and prostate cancer risk by using prospectively collected blood samples to join the collaboration. Thirteen studies collected data on circulating IGF concentrations and the subsequent risk for prostate cancer (5, 6, 820), of which 1 contributed only data on sex hormones (20). Eleven of the studies used a matched casecontrol design nested within a prospective cohort study (5, 6, 812, 16, 19) or a randomized trial (1315, 17). One study used a casecohort design (18) and was converted into a matched casecontrol design by randomly matching up to 3 control participants to each case patient by age at recruitment, time between blood collection and diagnosis, time of blood draw, and race. (Table 1 provides a full description of the studies and matching criteria used.) Most of the prospective studies were population-based, with the exception of 1 based on health plan members (9), 1 that recruited male health professionals (16), and 1 that was a combination of an intervention study and a monitoring study for cardiovascular disease (6, 10). Two of the randomized trials did not have prostate cancer as a primary end point (5, 8, 15); the other 2 were based within a screening trial (13) or were about treatment of prostate-specific antigen (PSA)detected prostate cancer (14). Table 1. Study Characteristics Individual participant data were available for age; height; weight; smoking status; alcohol consumption; marital status; socioeconomic status (assessed by educational achievement); race; concentrations of IGFs, IGFBPs, and endogenous sex steroids; and PSA level. Information sought about prostate cancer included date of diagnosis, stage and grade of disease, and method of case patient ascertainment. Some studies (5, 6, 8, 10, 16) published more than 1 article or performed assays at different times on the association between IGFs and prostate cancer risk, sometimes with different matched casecontrol sets, laboratory measurements, and durations of follow-up. For each study, we created a single data set in which each participant appeared only once. In our analysis, we treated any participant who appeared in a study as both a control participant and a case patient as a case patient only. We removed matched set identifiers, and we generated a series of strata (equivalent to matched sets) in which participants in each study were grouped according to age at recruitment (2-year age bands) and date of recruitment (by year), because these matching criteria were common to most studies (Table 1). The number of strata used in the collaborative analysis was slightly less than that of matched sets used in the original analyses. To ensure that this process did not introduce any bias, we checked that the results for each study, using the original matched sets, were the same as those using the strata described above. Tumors were classified as advanced if the tumor was described as extending beyond the prostate capsule (T3/T4), and/or there was lymph node involvement (N1/N2/N3), and/or there were distant metastases (M1); tumors were classified as localized if they were T0/T1/T2 and N0/NX and M0. We classified tumors as high-grade if they had a Gleason score of 7 or more or were moderately poorly or poorly differentiated; otherwise, they were classified as low-grade. Statistical Analysis We calculated partial correlation coefficients between log-transformed IGF and IGFBP concentrations among control participants, adjusted for age at blood collection (<50, 50 to 59, 60 to 69, or 70 years) and study. For each IGF and IGFBP, we categorized men into quintiles of IGF and IGFBP serum concentrations, with cut-points defined by the study-specific quintiles of the distribution within control participants. For studies with more than 1 publication or in which the serum assays were done at different times, resulting in different absolute levels of IGFs (5, 6, 8, 10, 16), we calculated cut-points separately for each substudy. We used a conditional logistic regression stratified by study, age at recruitment (2-year age bands), and date of recruitment (single year) as our main method of analysis. To provide a summary measure of risk, we calculated a linear trend by scoring the quintiles of the serum IGF or IGFBP concentrations as 0, 0.25, 0.5, 0.75, and 1. Under the assumption of linearity, a unit change in this trend variable is equivalent to the odds ratio (OR) comparing the highest with the lowest quintile. All results are unadjusted for participant characteristics, except for those controlled by the stratification variables. We examined the possible influence of 5 participant characteristics by adjusting the relevant conditional logistic regression models for body mass index (BMI) (<22.5, 22.5 to 24.9, 25.0 to 27.4, 27.5 to 29.9, or >30 kg/m2), marital status (married or cohabiting, or not married or cohabiting), educational status (did not attend college or university, or attended college or university), smoking (never, previous, or current), and alcohol consumption (<10 or 10 g/d). We excluded participants from the analysis if they had a missing value for the characteristic under examination. We assessed heterogeneity in linear trends among studies by using a chi-square statistic to test whether the study-specific ORs were statistically different from the overall OR (21). Heterogeneity among studies was also quantified by calculating the H and I 2 statistics (22). To test whether the linear trend OR estimates for each IGF and IGFBP varied according to case patient characteristics, we estimated a series of subsets for each characteristic: stage at diagnosis (localized or advanced), grade at diagnosis (low or high), year of diagnosis (before 1990, 1990 to 1994, or 1995 onward; these year cutoffs were chosen to attempt to reflect differences in the use of the PSA test for cancer detection), age at diagnosis (<60, 60 to 69, or 70 years), and time between blood collection and diagnosis (<3, 3 to 6, or 7 years). We excluded case patients from the analyses of stage and grade at diagnosis if the relevant information was not available. For each of these case patient characteristics, we calculated a heterogeneity chi-square statistic to assess whether the estimated ORs statistically differed from each other (21). To assess whether the OR estimate of the linear trend for each IGF or IGFBP varied according to PSA level at recruitment (<2 g/L or 2 g/L), we entered an interaction term into the conditional logistic regression model for each IGF or IGFBP, and we tested the statistical significance of the interaction term with a likelihood ratio test. Statistical significance was set at the 5% level. All statistical tests were 2-sided. All statistical analyses were done with Stata, version 9.0 (StataCorp, College Station, Texas). Results Table 1 shows the characteristics of the studies. The 12 prospective studies included approximately 3700 case patients with prostate cancer and 5200 control participants. Insulin-like growth factor I and IGFBP-III measurements were available for all and 3600 case patients, respectively. However, IGF-II and IGFBP-II measurements were available for only 379 and 419 case patients, respectively (Table 2). Mean age at blood collection

Assessment and Control for Confounding by Indication in Observational Studies

In the evaluation of pharmacologic therapies, the controlled clinical trial is the preferred design. When clinical trial results are not available, the alternative designs are observational epidemiologic studies. A traditional concern about the validity of findings from epidemiologic studies is the possibility of bias from uncontrolled confounding. In studies of pharmacologic therapies, confounding by indication may arise when a drug treatment serves as a marker for a clinical characteristic or medical condition that triggers the use of the treatment and that, at the same time, increases the risk of the outcome under study. Confounding by indication is not conceptually different from confounding by other factors, and the approaches to detect and control for confounding — matching, stratification, restriction, and multivariate adjustment — are the same. Even after adjustment for known risk factors, residual confounding may occur because of measurement error or unmeasured or unknown risk factors. Although residual confounding is difficult to exclude in observational studies, there are limits to what this “unknown” confounding can explain. The degree of confounding depends on the prevalence of the putative confounding factor, the level of its association with the disease, and the level of its association with the exposure. For example, a confounding factor with a prevalence of 20% would have to increase the relative odds of both outcome and exposure by factors of 4 to 5 before the relative risk of 1.57 would be reduced to 1.00. Observational studies have provided important scientific evidence about the risks associated with several risk factors, including drug therapies, and they are often the only option for assessing safety. Understanding the methods to detect and control for confounding makes it possible to assess the plausibility of claims that confounding is an alternative explanation for the findings of particular studies. J Am Geriatr Soc 47:749–754, 1999.

The role of poultry and meats in the etiology of Campylobacter jejuni/coli enteritis

To determine the role of meats as possible sources of infection leading to Campylobacter jejuni/coli (CJC) enteritis, 218 cases and 526 controls were selected from the King County Group Health Cooperative (GHC) population from April 1982 through September 1983. All subjects were interviewed regarding food consumption one week prior to case onset. Consumption of chicken and cornish game hen were both associated with more than a doubling of the risk of CJC enteritis: for chicken (relative risk = 2.4, 95% CI = 1.6-3.6), and for game hen, (RR = 3.3, 95% CI = 1.1-9.8). The consumption of raw or rare chicken was even more strongly associated (RR = 7.6, 95% CI = 2.1-27.6). Strains of CJC bearing R factors for tetracycline were equally as likely as tetracycline-susceptible strains to have been acquired from chicken and game hens. Processed turkey sandwich meats (RR = 1.7, 95% CI = 1.0-2.9) raw or rare fish (RR = 4.0, 95% CI = 1.1-14.5) and shellfish (RR = 1.5, 95% CI = 1.1-2.1) were the only other meats reported to have been eaten significantly (p less than .05) more often by cases than by controls. These data along with the results of bacteriologic sampling of meats from King County retail food markets during the same period suggest that ingestion of contaminated chicken is a primary source of CJC enteritis, contributing to approximately half of the cases.