Changing population characteristics, effect-measure modification, and cancer risk factor identification

Epidemiologic studies have identified a number of lifestyle factors, e.g. diet, obesity, and use of certain medications, which affect risk of colon cancer. However, the magnitude and significance of risk factor-disease associations differ among studies. We propose that population trends of changing prevalence of risk factors explains some of the variability between studies when factors that change prevalence also modify the effect of other risk factors. We used data collected from population-based control who were selected as study participants for two time periods, 1991–1994 and 1997–2000, along with data from the literature, to examine changes in the population prevalence of aspirin and non-steroidal anti-inflammatory medication (NSAID) use, obesity, and hormone replacement therapy (HRT) over time. Data from a population-based colon cancer case-control study were used to estimate effect-measurement modification among these factors. Sizeable changes in aspirin use, HRT use, and the proportion of the population that is obese were observed between the 1980s and 2000. Use of NSAIDs interacted with BMI and HRT; HRT use interacted with body mass index (BMI). We estimate that as the prevalence of NSAIDs use changed from 10% to almost 50%, the colon cancer relative risk associated with BMI >30 would change from 1.3 to 1.9 because of the modifying effect of NSAIDs. Similarly, the relative risk estimated for BMI would increase as the prevalence of use of HRT among post-menopausal women increased. In conclusion, as population characteristics change over time, these changes may have an influence on relative risk estimates for colon cancer for other exposures because of effect-measure modification. The impact of population changes on comparability between epidemiologic studies can be kept to a minimum if investigators assess exposure-disease associations within strata of other exposures, and present results in a manner that allows comparisons across studies. Effect-measure modification is an important component of data analysis that should be evaluated to obtain a complete understanding of disease etiology

Gene Expression Profiling of a Mouse Model of Pancreatic Islet Dysmorphogenesis

In the past decade, several transcription factors critical for pancreas organogenesis have been identified. Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized. Previous studies have shown that transgenic over-expression of the transcription factor Hnf6 specifically in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf6 causes defects in islet morphogenesis have yet to be elucidated.We exploited the dysmorphic islets in Hnf6 transgenic animals as a tool to identify factors important for islet morphogenesis. Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals. Here we report the identification of genes with an altered expression in Hnf6 transgenic animals and highlight factors with potential importance in islet morphogenesis. Importantly, gene products involved in cell adhesion, cell migration, ECM remodeling and proliferation were found to be altered in Hnf6 transgenic pancreata, revealing specific candidates that can now be analyzed directly for their role in these processes during islet development.This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function

Tamoxifen-Induced Cre-loxP Recombination Is Prolonged in Pancreatic Islets of Adult Mice

Tamoxifen (Tm)-inducible Cre recombinases are widely used to perform gene inactivation and lineage tracing studies in mice. Although the efficiency of inducible Cre-loxP recombination can be easily evaluated with reporter strains, the precise length of time that Tm induces nuclear translocation of CreERTm and subsequent recombination of a target allele is not well defined, and difficult to assess. To better understand the timeline of Tm activity in vivo, we developed a bioassay in which pancreatic islets with a Tm-inducible reporter (from Pdx1PB-CreERTm;R26RlacZ mice) were transplanted beneath the renal capsule of adult mice previously treated with three doses of 1 mg Tm, 8 mg Tm, or corn oil vehicle. Surprisingly, recombination in islet grafts, as assessed by expression of the β-galactosidase (β-gal) reporter, was observed days or weeks after Tm treatment, in a dose-dependent manner. Substantial recombination occurred in islet grafts long after administration of 3×8 mg Tm: in grafts transplanted 48 hours after the last Tm injection, 77.9±0.4% of β-cells were β-gal+; in β-cells placed after 1 week, 46.2±5.0% were β-gal+; after 2 weeks, 26.3±7.0% were β-gal+; and after 4 weeks, 1.9±0.9% were β-gal+. Islet grafts from mice given 3×1 mg Tm showed lower, but notable, recombination 48 hours (4.9±1.7%) and 1 week (4.5±1.9%) after Tm administration. These results show that Tm doses commonly used to induce Cre-loxP recombination may continue to label significant numbers of cells for weeks after Tm treatment, possibly confounding the interpretation of time-sensitive studies using Tm-dependent models. Therefore, investigators developing experimental approaches using Tm-inducible systems should consider both maximal recombination efficiency and the length of time that Tm-induced Cre-loxP recombination occurs

Correlates of urinary albumin excretion in young adult Blacks and Whites: The Coronary Artery Risk Development in Young Adults Study

The rate of urinary albumin excretion is an important risk factor for kidney failure, stroke, and cardiovascular disease, perhaps because higher albumin excretion reflects endothelial cell dysfunction. The authors characterized urinary albumin excretion according to blood pressure, diabetes mellitus, and other factors in 2,582 Black and White participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study who were aged 18-30 years in 1985-1986. Urinary albumin and creatinine concentrations were determined using single untimed samples 10 and 15 years later. The albumin:creatinine ratio was analyzed as a continuous variable and a dichotomous variable (higher albumin excretion, including microalbuminuria (25-249 mg/g) and macroalbuminuria (≥250 mg/g)). Seventy percent of persons with increased albumin excretion were both normoglycemic and normotensive (systolic/diastolic blood pressure \u3c140/90 mmHg and no use of antihypertensive drugs). Even when diabetic subjects, who have greater risk, were excluded, albumin excretion rose continuously as blood pressure increased among Blacks; increases started at systolic/diastolic blood pressures of 130/85 mmHg among Whites. Furthermore, blood pressure measured up to 15 years earlier predicted incident higher albumin excretion at year 15. These findings persisted after adjustment for age, body mass index, smoking, and blood lipid and plasma insulin levels. A risk of higher urinary albumin excretion exists at blood pressure levels below those commonly regarded as hypertension, with a greater risk among Blacks than among Whites

Gender- and race-specific determination of albumin excretion rate using albumin-to-creatinine ratio in single, untimed urine specimens: The Coronary Artery Risk Development in Young Adults Study

Although albumin excretion rate is commonly estimated by using albumin/creatinine ratio (A/C), gender and race differences in creatinine excretion may bias this estimate. The authors optimize the use of an untimed (spot) urine specimen among 3,371 Blacks and Whites aged 28-40 years in the Coronary Artery Risk Development in Young Adults Study in 1995-1996. Using three 24-hour collections during the year 5 examination, they determined k = 0.68 x 0.88 in Black men, 0.88 in Black women, 0.68 in White men, and 1.0 in White women to reflect gender and race differences in creatinine excretion. The authors then computed A/C adjusted for race and sex differences in creatinine excretion (A/kC) by using an untimed urine sample in the year 10 examination. A/kC ≥ 25 mg/g (194 cases of microalbuminuria and 26 cases of clinical grade albuminuda) was more common among Blacks (9.1%) than among Whites (4.2%) and among men (8.2%) than among women (5.0%). Use of the unadjusted A/C underestimated the prevalence of microalbuminuria among men by 52% and among Blacks by 26%. Adjustment of A/C permitted more accurate estimation of albumin excretion rate. Men and Blacks have a higher albumin excretion rate than do women and Whites and may thereby have an increased risk of microvascular and macrovascular disease

Phone-based motivational interviewing to increase self-efficacy in individuals with phenylketonuria

Objective: To measure change in patient activation and self-efficacy in individuals with phenylketonuria (PKU) before and after a 6-month phone-based motivational interviewing (MI) intervention and determine the feasibility of implementing dietary counseling for PKU using an MI approach. Methods: Participants (n = 31) included preadolescents (7–12 years), adolescents (13–17 years), and adults (18–35 years) with early-treated PKU. Participants completed online questionnaires assessing self-reported stage of change (SOC), patient activation, and self-efficacy for PKU self-management behaviors. The intervention included monthly phone-based dietary counseling using MI during which participants set monthly goals. Results: Patient activation and self-efficacy were significantly different by age group (both p < 0.01) with higher scores in older participants. Self-efficacy significantly increased from baseline to month 6 among adolescents and adults (7.4 ± 1.9 and 8.6 ± 1.3, respectively, p = 0.002). Preadolescents did not have a significant change in self-efficacy (p = 0.79). There was no increase in patient activation for preadolescents or adolescents/adults (p = 0.19 and p = 0.24, respectively). Indicators of learning problems were not significantly associated with self-efficacy (p = 0.33) or patient activation (p = 0.83). Conclusion: These results demonstrate the feasibility of implementing phone-based dietary counseling for PKU using MI. This study also supports further investigation of MI as an intervention approach to improving self-efficacy and self-management behaviors in adolescents and adults with PKU

Associations of Dietary Protein and Energy Intakes With Protein-Energy Wasting Syndrome in Hemodialysis Patients

The associations of dietary protein and/or energy intakes with protein or energy wasting in patients on maintenance hemodialysis are controversial. We examined these in the Hemodialysis (HEMO) Study. Methods: In 1487 participants in the HEMO Study, baseline dietary protein intake (grams per kilogram per day) and dietary energy intake (kilocalories per kilograms per day) were related to the presence of the protein-energy wasting (PEW) syndrome at month 12 (defined as the presence of at least 1 criteria in 2 of the 3 categories of low serum chemistry, low body mass, and low muscle mass) in logistic regression models. In additional separate models, protein intake estimated from equilibrated normalized protein catabolic rate (enPCR) was also related to the PEW syndrome. Results: Compared with the lowest quartile, the highest quartile of baseline dietary protein intake was paradoxically associated with increased risk of the PEW syndrome at month 12 (odds ratio [OR]: 4.11; 95% confidence interval [CI]: 2.79–6.05). This relationship was completely attenuated (OR: 1.35; 95% CI: 0.88–2.06) with adjustment for baseline body weight, which suggested mathematical coupling. Results were similar for dietary energy intake. Compared with the lowest quartile of baseline enPCR, the highest quartile was not associated with the PEW syndrome at 12 months (OR: 0.78; 95% CI: 0.54–1.12). Discussion: These data do not support the use of dietary protein intake or dietary energy intake criteria in the definition of the PEW syndrome in patients on maintenance hemodialysis