Commentary: Trade-offs in the development of a sample design for case-control studies

The recent article, "Comparison of Telephone Sampling and Area Sampling: Response Rates and Within-Household Coverage" (Am J Epidemiol 2001;153:1119-27), raised a number of issues related to two sampling methodologies that can be used for selecting population-based controls for case-control studies: random digit dialing (RDD) and area probability sampling. Some of these issues are discussed in this commentary in more detail to help in making sample design decisions, including the need to take the analysis plan into account when developing a sample design. Data from the paper are used to illustrate how the choice of sample design can affect analyses. Relative costs associated with the two methodologies as well as variance and bias concerns are also discussed in detail. Sample coverage issues, including those associated with list-assisted RDD, are considered, as are some advantages of the list-assisted approach. A discussion of the use of concurrent screening and sampling with an RDD approach as an alternative to periodically selecting fixed sample sizes is provided.     

Breast cancers among very young premenopausal women (United States)

Objective: To assess risk factors for breast cancer among very young compared to older premenopausal women. Methods: Between 1990 and 1992 a population-based case–control study conducted in Atlanta, GA, Seattle/Puget Sound, WA, and central NJ interviewed 3307 premenopausal women aged 20–54 years. Logistic regression models estimated adjusted relative risks (RR) and 95% confidence intervals (CI) for each of three 10-year age groups. Results: Among the youngest age group (<35 years, n = 545), significant predictors of risk included African-American race (RR = 2.66; 95% CI 1.4–4.9) and recent use of oral contraceptives (RR = 2.26; 95% CI 1.4–3.6). Although these relationships were strongest for estrogen receptor-negative (ER–) tumors (RRs of 3.30 for race and 3.56 for recent oral contraceptive use), these associations were also apparent for young women with ER+ tumors. Delayed childbearing was a risk factor for ER+ tumors among the older premenopausal women (p _trend < 0.01), but not for women <35 years in whom early childbearing was associated with an increased risk, reflecting a short-term increase in risk immediately following a birth. Family history of early-onset breast cancer was more strongly associated with risk among women <35 years (RR = 3.22) than those 45–54 years (RR = 1.51). Risk factors for premenopausal breast cancer not significantly modified by age at diagnosis included early age at menarche, low body mass index, and heavy alcohol consumption. Conclusion: These findings suggest the possibility that women who develop breast cancers at very young ages may be etiologically as well as clinically distinct.     

FLK-1-based minigene vaccines induce T cell-mediated suppression of angiogenesis and tumor protective immunity in syngeneic BALB/c mice

Angiogenesis is a rate-limiting step in the development of tumors. Here, we demonstrate that oral minigene DNA vaccines against murine vascular endothelial growth factor receptor-2 (FLK-1), a self-antigen overexpressed on proliferating endothelial cells in the tumor vasculature, induced protection against tumors of different origin in syngeneic BALB/c mice. This protection is mediated by CD8 T cells, which specifically kill FLK-1(+) endothelial cells, resulting in marked suppression of tumor angiogenesis. More importantly, the minigene vaccine proved to be of similar efficacy as a vaccine encoding the whole FLK-1 gene. These data suggest a FLK-1 minigene vaccine provides a more flexible alternative to the whole gene vaccine and will facilitate their future design and clinical applications in cancer therapy and prevention.     

Improved formulation of a recombinant ricin A-chain vaccine increases its stability and effective antigenicity

Ricin is a potent toxin associated with bioterrorism for which no vaccine or specific countermeasures are currently available. A stable, non-toxic and immunogenic recombinant ricin A-chain vaccine (RTA 1-33/44-198) has been developed by protein engineering. We identified optimal formulation conditions for this vaccine under which it remained stable and potent in storage for up to 18 months, and resisted multiple rounds of freeze-thawing without stabilizing co-solvents. Reformulation from phosphate buffer to succinate buffer increased adherence of the protein to aluminum hydroxide adjuvant from 15 to 91%, with a concomitant increase of nearly threefold in effective antigenicity in a mouse model. Using Fourier-transform infrared spectroscopy, we examined the secondary structure of the protein while it was adhered to aluminum hydroxide. Adjuvant adsorption produced only a small apparent change in secondary structure, while significantly stabilizing the protein to thermal denaturation. The vaccine therefore may be safely stored in the presence of adjuvant. Our results suggest that optimization of adherence of a protein antigen to aluminum adjuvant can be a useful route to increasing both stability and effectiveness, and support a role for a "depot effect" of adjuvant.     

Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer.

PURPOSE: The paclitaxel, fluorouracil, and hydroxyurea regimen of paclitaxel, infusional fluorouracil, hydroxyurea, and twice-daily radiation therapy (TFHX) administered every other week has resulted in 3-year survival rates of 60% of stage IV patients. Locoregional and distant failure rates were 13% and 23%, respectively. To reduce distant failure rates, we added a brief course of induction chemotherapy to TFHX. PATIENTS AND METHODS: Sixty-nine patients received six weekly doses of carboplatin (AUC2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. RESULTS: Ninety-six percent had stage IV disease. Response to induction chemotherapy was partial response 52% and complete response (CR) 35%. Symptomatically, there was a significant reduction in mouth and throat pain. The most common grade 3 or 4 toxicity was neutropenia (36%). Best response following completion of TFHX was CR in 83%. Toxicities of TFHX consisted of grade 3 or 4 mucositis (74% and 2%) and dermatitis (47% and 14%). At a median follow-up of 28 months, locoregional or systemic disease progression were each noted in five patients. The overall 3-year progression-free survival was 80% (95% confidence interval [CI], 71% to 90%), and the 2- and 3-year overall survival rates were 77% (95% CI, 66% to 87%) and 70% (95% CI, 59% to 82%), respectively. At 12 months, five patients were completely feeding-tube dependent. CONCLUSION: Administration of carboplatin and paclitaxel before TFHX chemoradiotherapy results in high response activity and may decrease distant failure rates. Overall survival, progression, and organ preservation/functional outcome data support definitive evaluation of this approach.     

Eight channel scanning and timing controller for physiological data aquisition

A system is described which enables the sequential conversion into digital form, and printing or punching on paper tape of up to eight channels of physiological data. A control unit allows the selection of an acquisition-window time for each successive channel of data, programs the measurement parameters, and switches in the appropriate signal line. The system will accept mixed analogue data, i.e. continuous slowly-varying signals (ECG, EEG, temperature, etc.) as well as pulse data (action potentials, etc.), and is capable of direct analogue-to-digital conversion, or of the counting functions: totalizing, time interval between pulses, period, etc. The basic DAS components are standard Hewlett-Packard instruments. The controller is assembled from Digital Equipment Corporation M-series digital modules.     

Establishment and Characterization of a New Ph1-Positive Chronic Myeloid Leukemia Cell Line MC3 with Trilineage Phenotype and an Altered p53 Gene

A new Ph¹-positive leukemic cell line (MC3) expressing the P210^ber/abl oncoprotein was established from a patient with CML in blast crisis. The MC3 cells showed the trilineage phenotype of myeloid, lymphoid (CD 19) and megakaryocytoid lineages, and had a proliferative response to rhIL-1 and rhIL-3 in the serum-free culture. These results and the expression of CD34 indicated that the MC3 cells have characteristics of hematopoietic progenitor cells. Recently, it has been documented that alterations of the p53 gene in leukemic cells are frequently detected during the blast crisis of CML. The MC3 cells contained the altered p53 gene. In addition, the original leukemic cells showed the point-mutational activation of the N-ras gene and an additional chromosomal abnormality inv(3q), but the MC3 cells contained no such abnormalities, indicating that not all of the original leukemic cells had these abnormalities. Thus, the MC3 cell line may provide several insights into investigations of the blast crisis in CML as well as hematopoietic progenitor cells.     

Fertility among testicular cancer survivors: a case-control study in the U.S.

Introduction

Testicular germ cell tumors (TGCT) disproportionately affect men between the ages of 15 and 49 years, when reproduction is typical. Although TGCT treatment directly affects gonadal tissues, it remains unclear whether there are long-term effects on fertility.

Methods

To examine post-TGCT treatment fertility, study participants in a previously conducted case-control study were contacted. The men were initially enrolled in the US Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) study between 2002 and 2005. A total of 246 TGCT cases and 236 controls participated in the current study and completed a self-administered questionnaire in 2008–2009.

Results

TGCT cases were significantly more likely than controls to experience fertility distress (OR 5.23; 95% CI 1.99–13.76) and difficulty in fathering children (OR 6.41; 2.72–15.13). Cases were also more likely to be tested for infertility (OR 3.65; 95% CI 1.55–8.59). Cases, however, did not differ from controls in actually fathering children (OR 1.37; 95% CI 0.88–2.15). These findings were predominantly observed among nonseminoma cases and cases treated with surgery only or surgery-plus-chemotherapy.

Discussion

While expressing greater fertility distress, higher likelihood of fertility testing, and difficulty fathering children, these data suggest that TGCT survivors are no less likely to father children than are other men. It is possible that treatment for TGCT does not permanently affect fertility or, alternatively, that TGCT survivors attempt to father children with greater persistence or at younger ages than do other men.