Epidemiologic Evaluation of Measurement Data in the Presence of Detection Limits

Quantitative measurements of environmental factors greatly improve the quality of epidemiologic studies but can pose challenges because of the presence of upper or lower detection limits or interfering compounds, which do not allow for precise measured values. We consider the regression of an environmental measurement (dependent variable) on several covariates (independent variables). Various strategies are commonly employed to impute values for interval-measured data, including assignment of one-half the detection limit to nondetected values or of “fill-in” values randomly selected from an appropriate distribution. On the basis of a limited simulation study, we found that the former approach can be biased unless the percentage of measurements below detection limits is small (5–10%). The fill-in approach generally produces unbiased parameter estimates but may produce biased variance estimates and thereby distort inference when 30% or more of the data are below detection limits. Truncated data methods (e.g., Tobit regression) and multiple imputation offer two unbiased approaches for analyzing measurement data with detection limits. If interest resides solely on regression parameters, then Tobit regression can be used. If individualized values for measurements below detection limits are needed for additional analysis, such as relative risk regression or graphical display, then multiple imputation produces unbiased estimates and nominal confidence intervals unless the proportion of missing data is extreme. We illustrate various approaches using measurements of pesticide residues in carpet dust in control subjects from a case–control study of non-Hodgkin lymphoma

Human Leukocyte Antigen Class I and II Alleles and Overall Survival in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Genetic variation in the 6p21 chromosomal region, including human leukocyte antigen (HLA) genes and tumor necrosis factor (TNF), has been linked to both etiology and clinical outcomes of lymphomas. We estimated the effects of HLA class I (A, B, and C), class II DRB1 alleles, and the ancestral haplotype (AH) 8.1 (HLAA*01-B*08-DRB1*03-TNF-308A) on overall survival (OS) among patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in a population-based study of non-Hodgkin lymphoma. During a median followup of 89 months, 31% (52 of 166) DLBCL and 28% (46 of 165) FL patients died. Using multivariate Cox regression models, we observed statistically significant associations between genetic variants and survival: HLA-Cw*07:01 was associated with poorer OS among DLBCL patients (Hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.01–3.05); HLA-A*01:01 was associated with poorer OS (HR = 2.23, 95% CI = 1.24–4.01), and HLA-DRB1*13 (HR = 0.12, 95% CI = 0.02–0.90) and HLA-B Bw4 (HR = 0.36, 95% CI = 0.20–0.63) with better OS among FL patients. These results support a role for HLA in the prognosis of DLBCL and FL and represent a promising class of prognostic factors that warrants further evaluation

Evaluating the impact of eligibility criteria in first-line clinical trials for follicular lymphoma: A MER/LEO cohort analysis

Cancer clinical trial eligibility criteria may create patient populations studied in trials that do not reflect the patient populations treated in the real-world setting. Follicular lymphoma (FL) is an indolent lymphoma with heterogeneous presentations across a broad range of individuals, resulting in many acceptable management strategies. We evaluated how first-line clinical trial eligibility criteria impacted the demographic makeup and outcomes of patients with FL for whom systemic therapy might be considered. We compared the characteristics of 196 patients with FL from a single institution to eligibility criteria from 10 first-line FL trials on clinicaltrials.gov. Next, we tabulated eligibility criteria from 24 first-line FL protocols and evaluated their impact on 1198 patients with FL with stages II to IV disease from the prospective Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO) cohort studies. We found that 39.8% and 52.7% of patients with FL might be excluded from clinical trials based on eligibility criteria derived from clinicaltrials.gov and protocol documents, respectively. Patients excluded because of renal function, prior malignancy, and self-reported serious health conditions tended to be older. Expanding stage requirement from III-IV to II-IV, and platelet requirement from ≥150 000 to ≥75 000 increased population size by 21% and 8%, respectively, in MER and by 16% and 13%, respectively, in LEO, without impacting patient demographics or outcomes. These data suggest that management of older individuals with FL may not be fully informed by recent clinical trials. Moreover, liberalizing stage and platelet criteria might expand the eligible population and allow for quicker trial accrual without impacting outcomes

Genome-Wide Transcriptional Profiling Reveals MicroRNA-Correlated Genes and Biological Processes in Human Lymphoblastoid Cell Lines

Expression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and used loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs.To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q<0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological processes related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.This study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations

Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies.

INTRODUCTION: The stroma is the supportive framework of biologic tissue in the breast, consisting of various proteins such as the proteoglycans, decorin and lumican. Altered expression of decorin and lumican is associated with breast tumors. We hypothesized that genetic variation in the decorin (DCN) and lumican (LUM) genes may contribute to breast cancer. METHODS: We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)). RESULTS: In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (P trend <or= 0.05). The association with LUM rs2268578, evaluated further in SEARCH, was positive, although the odds ratios (OR) were weaker and not statistically significant. ORs were 1.4 (95% confidence interval [CI], 1.1 to 1.8) for heterozygotes and 2.2 (95% CI, 1.1 to 4.3; P2 df = 0.002) for homozygotes in the Mayo Clinic sample, and were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.4 (95% CI, 1.0 to 2.1; P2 df = 0.13) for homozygotes in the SEARCH sample. In combined analyses, the ORs were 1.1 (95% CI, 1.0 to 1.2) for heterozygotes and 1.6 (95% CI, 1.2 to 2.3; P2 df = 0.005) for homozygotes. Positive associations for this polymorphism were observed for estrogen receptor-positive tumors in both the Mayo Clinic sample (OR for heterozygotes = 1.5, 1.1 to 1.9 and OR for homozygotes = 2.5, 1.2 to 5.3;P2 df = 0.001) and the SEARCH sample (OR for heterozygotes = 1.0, 0.9 to 1.1 and OR for homozygotes = 1.6, 1.0 to 2.5; P2 df = 0.10). In combined analyses, the ORs were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.9 (95% CI, 1.3 to 2.8; P2 df = 0.001) for homozygotes. CONCLUSIONS: Although LUM rs2268578 was associated with breast cancer in the Mayo Clinic study, particularly estrogen receptor-positive breast cancer, weaker and modest associations were observed in the SEARCH sample. These modest associations will require larger samples to adequately assess the importance of this polymorphism in breast cancer

Blood transfusion history and risk of non-Hodgkin lymphoma : an InterLymph pooled analysis

PURPOSE: To conduct a pooled analysis assessing the association of blood transfusion with risk of non-Hodgkin lymphoma (NHL). METHODS: We used harmonized data from 13 case-control studies (10,805 cases, 14,026 controls) in the InterLymph Consortium. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusted for study design variables. RESULTS: Among non-Hispanic whites (NHW), history of any transfusion was inversely associated with NHL risk for men (OR 0.74; 95% CI 0.65-0.83) but not women (OR 0.92; 95% CI 0.83-1.03), pheterogeneity = 0.014. Transfusion history was not associated with risk in other racial/ethnic groups. There was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion, and further adjustment for socioeconomic status, body mass index, smoking, alcohol use, and HCV seropositivity did not alter the results. Associations for NHW men were stronger in hospital-based (OR 0.56; 95% CI 0.45-0.70) but still apparent in population-based (OR 0.84; 95% CI 0.72-0.98) studies. CONCLUSIONS: In the setting of a literature reporting mainly null and some positive associations, and the lack of a clear methodologic explanation for our inverse association restricted to NHW men, the current body of evidence suggests that there is no association of blood transfusion with risk of NHL

Analysis of Environmental Chemical Mixtures and Non-Hodgkin Lymphoma Risk in the NCI-SEER NHL Study

Background: There are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals (i.e., one-by-one). Objectives: We determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk. Methods: We conducted a population-based case–control study of NHL in four National Cancer Institute–Surveillance, Epidemiology, and End Results centers—Detroit, Michigan; Iowa; Los Angeles County, California; and Seattle, Washington—from 1998 to 2000. We used weighted quantile sum (WQS) regression to model the association of a mixture of chemicals and risk of NHL. The WQS index was a sum of weighted quartiles for 5 polychlorinated biphenyls (PCBs), 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical mixture weights and effects for study sites combined and for each site individually, and also for histologic subtypes of NHL. Results: The WQS index was statistically significantly associated with NHL overall [odds ratio (OR) = 1.30; 95% CI: 1.08, 1.56; p = 0.006; for one quartile increase] and in the study sites of Detroit (OR = 1.71; 95% CI: 1.02, 2.92; p = 0.045), Los Angeles (OR = 1.44; 95% CI: 1.00, 2.08; p = 0.049), and Iowa (OR = 1.76; 95% CI: 1.23, 2.53; p = 0.002). The index was marginally statistically significant in Seattle (OR = 1.39; 95% CI: 0.97, 1.99; p = 0.071). The most highly weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly weighted chemicals varied by study site; PCBs were more highly weighted in Detroit, and pesticides were more highly weighted in Iowa. Conclusions: An index of chemical mixtures was significantly associated with NHL. Our results show the importance of evaluating chemical mixtures when studying cancer risk

A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling

A BAFF receptor mutation associated with non-Hodgkin lymphoma provides new insight into the proximal players of normal BAFF-R signaling