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Background: Human T-cell lymphotropic virus type I (HTLV-I) is linked to adult T-cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy (HAM; also known as tropical spastic paraparesis [TSP]), a chronic neurodegenerative disorder. Worldwide, several million HTLV-I carriers are at risk for disease, with an estimated lifetime cumulative risk of 1%-5%. However, the determinants of disease progression are relatively unknown. We studied human leukocyte antigens (HLA class II) that have been implicated in the pathogenesis of HTLV-I-related diseases.Methods: We analyzed HLA class II alleles among asymptomatic HTLV-I carriers (n = 45), patients with ATL (n = 49) or HAM/TSP (n = 54), and HTLV-I seronegative control subjects (n = 51). All participants were of African descent and were enrolled in epidemiologic studies conducted at the University of the West Indies, Kingston, Jamaica. We used standard microlymphocytotoxicity assays for HLA antigen serotyping and polymerase chain reaction-based methods to examine HLA class II DRB1 and DQB1 alleles.Results: Two antigens determined by serotyping, DR15 and DQ1, occurred at significantly increased frequency among HTLV-I carriers compared with seronegative control subjects (42% versus 22% for DR15 [odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.0-7.2] and 78% versus 53% for DQ1 [OR = 3.1; 95% CI = 1.2-8.5]). Asymptomatic carriers were shown to have an HLA class II allele distribution similar to that of patients with ATL, and the frequencies of the alleles DRB1*1501, DRB1*1101, and DQB1*0602 were significantly greater in patients with ATL and asymptomatic carriers than in patients with HAM/TSP. In addition, haplotypes DRB1*1101-DQB1*0301 and DRB1*1501-DQB1*0602 were significantly increased among patients with ATL compared with patients with HAM/TSP.Conclusions: These data suggest that host genetic background is an important factor in determining whether HTLV-I carriers develop either ATL or HAM/TSP. [ABSTRACT FROM AUTHOR]

Background: DCIS (ductal carcinoma in situ) is comprised of cancerous cells that are contained within the milk duct and separated from the stroma by a basement membrane. Akt ~ activation is implicated in breast cancer progression and also upregulated in 30% of DCIS lesions. We have previously shown that ß1-integrin inhibition enhanced the efficacy of ionizing radiation (IR) in invasive breast cancer, via an Akt-mediated effect. Radiation therapy ~ (RT) is commonly used to treat DCIS, resulting in a decrease in recurrence risk by 50%. However, DCIS still recurs in a substantial number of patients, and as invasive disease half of the time. This study aimed to identify the effects of IR on Akt-driven DCIS, and possible mechanisms underlying invasive progression in surviving cells. Materials and Methods: To model DCIS, we took advantage of the ability of non-invasive mammary epithelial cells, MCF10A that form duct-like structures in 3-dimensional laminin-rich extracellular matrix (3D lrECM), and overexpressed an activated myristoylated form of the serine/threonine kinase, Akt. The 3D lrECM cultured MCF10A-Akt cells show filled lumen and retained basal polarity, characteristic of DCIS lesions in vivo. After DCIS structures formed in 3D lrECM, cultures were exposed to 8 Gy IR. Confocal microscopy analysis, western blot analysis, matrigel chemoinvasion assay and matix degradation assay were performed to characterize the IR effect on luminal or basal cells of the DCIS like structures. Results: MCF10A-Akt structures post-8 Gy IR shows a significant increase in apoptosis measured by cleaved caspase-3 (n = 3, P < 0.05). When we propagated cells post-IR in 3D lrECM, an invasive phenotype emerged in a sub-population of survivors (n = 3, P < 0.01). We also confirmed that inhibitory antibodies to ß1-integrin suppressed the invasive phenotype that was induced by 8 Gy IR. In addition to this, invasion activity emerged by 8 Gy IR was inhibited by nuclear factor-kappaB (NF-κB) inhibitor JSH-23 (n = 3, P < 0.01). Finally, inhibition {kappa} of ß1-integrins or NF-κB translocation completely suppresses the formation of invasive colonies. Discussion: In present study, we found that inhibition of ß1-integrins abrogates the emergence of an invasive phenotype among surviving clones. Our current data suggest that regulation of ß1-integrin signaling via NF-κB plays an important role in the emergence of invasive disease after radiation, and may be an important clinical target. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-08. [ABSTRACT FROM AUTHOR]

Industrial hygienists often observe workers to determine who should be measured based on a predicted exposure level. Such evaluations are usually based on real-time observation, yet surprisingly little research has been conducted on what determinants of exposure industrial hygienists use to rank workers and whether the ranking is accurate. Accuracy of the ranking may also be affected by the observation process, which is limited when conditions in the workers' immediate environment are rapidly changing. An alternative to real-time observation is videotaping workers and evaluating the tapes at a later date. A pilot study was conducted using previously collected data to determine if workers could be ranked by exposure level utilizing a scoring system to rate videotaped work practices. Six farmers had been videotaped and their dermal exposures measured as they applied insecticide to hogs. In this study, scores were developed to rate the farmers' working conditions by exposure level. Two types of determinants were used to describe exposure: touching and work practices. Touching included the number of times parts of the body had contact with surfaces possibly contaminated with insecticide. Work practices included the types of clothing and protective equipment worn as well as specific practices used by the farmer (e.g., application method). Two raters conducted independent assessments of the videotape using the same criteria. One rater reviewed the tape twice. Agreement between the raters for the "touching" score was weak (intra-class coefficient (ICC) = 0.28), but there was excellent agreement between the two raters (ICC = 0.92) for overall quality of work practices. As expected, a greater number of touches was moderately correlated with an increase in total exposure (rs = 0.60) and there was a weak inverse relationship between protective work practices and the exposure under the clothing (rs = -0.26). All other relationships with exposure level were contrary to what was expected. Since videotapes provide the industrial hygienist with a record of work events and can capture details that might otherwise be missed or not considered they may play a useful role in exposure assessment, especially if carefully developed procedures are followed to overcome the limitations found by this pilot study.

We derive a likelihood score method for interval estimation of the intraclass version of the kappa coefficient of agreement with binary classification using a general theory of Bartlett (1953, Biometrika 40, 306-317). By exact evaluation, we investigate statistical properties of the score method, the chi-square goodness-of-fit procedure (Donner and Eliasziw, 1992, Statistics in Medicine 11, 1511-1519; Hale and Fleiss, 1993, Biometrics 49, 523-534), and a crude confidence interval for small and medium sample sizes. Actual coverage percentages of the score and chi-square methods are satisfactorily close to the nominal confidence coefficient, while that of the crude method is quite unsatisfactory. The expected length of the score method is shorter than that of the chi-square procedure when the response rate is very small or very large.

The clinical spectrum of herpes simplex virus (HSV) infections, ranging from asymptomatic to frequently distressing outbreaks, suggests that there may be immunologic determinants of disease severity that are associated with human leukocyte antigen (HLA) expression. A controlled, prospective study identified several major histocompatibility complex (MHC) class I and II antigens whose frequencies are associated with HSV-2 infection or with frequent symptomatic genital recurrences. Previous studies were hampered by the inability to serologically identify patients with asymptomatic HSV-2 infection. Clinical evaluation and Western blot assay were used to identify 3 subject cohorts: 1 with no prior HSV infections, 1 with HSV-2 antibodies but no recognized symptoms, and 1 with HSV-2 antibodies and frequent genital recurrences. Statistical comparisons of HLA frequencies among these cohorts showed associations of HLA-B27 and -Cw2 with symptomatic disease. Also, HLA-Cw4 was significantly associated with HSV-2 infection. These associations indicate that immunologic factors linked to the MHC influence the risk of HSV-2 infection and disease expression.

Power and sample-size formulas for testing the homogeneity of relative risks using the score method are presented. The homogeneity score test (Gart, 1985, Biometrika 72, 673-677) is formally equivalent to the Pearson chi-square test, although they look different. Results of this paper may be useful in assessing the validity of the model of a common relative risk before combining several 2 x 2 tables or in designing a prospective study for detecting heterogeneity of relative risks.

Background: Human T-cell lymphotropic virus type I (HTLV-I) is linked to adult T-cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy (HAM; also known as tropical spastic paraparesis [TSP]), a chronic neurodegenerative disorder. Worldwide, several million HTLV-I carriers are at risk for disease, with an estimated lifetime cumulative risk of 1%-5%. However, the determinants of disease progression are relatively unknown. We studied human leukocyte antigens (HLA class II) that have been implicated in the pathogenesis of HTLV-I-related diseases., Methods: We analyzed HLA class II alleles among asymptomatic HTLV-I carriers (n = 45), patients with ATL (n = 49) or HAM/TSP (n = 54), and HTLV-I seronegative control subjects (n = 51). All participants were of African descent and were enrolled in epidemiologic studies conducted at the University of the West Indies, Kingston, Jamaica. We used standard microlymphocytotoxicity assays for HLA antigen serotyping and polymerase chain reaction-based methods to examine HLA class II DRB1 and DQB1 alleles., Results: Two antigens determined by serotyping, DR15 and DQ1, occurred at significantly increased frequency among HTLV-I carriers compared with seronegative control subjects (42% versus 22% for DR15 [odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.0-7.2] and 78% versus 53% for DQ1 [OR = 3.1; 95% CI = 1.2-8.5]). Asymptomatic carriers were shown to have an HLA class II allele distribution similar to that of patients with ATL, and the frequencies of the alleles DRB1*1501, DRB1*1101, and DQB1*0602 were significantly greater in patients with ATL and asymptomatic carriers than in patients with HAM/TSP. In addition, haplotypes DRB1*1101-DQB1*0301 and DRB1*1501-DQB1*0602 were significantly increased among patients with ATL compared with patients with HAM/TSP., Conclusions: These data suggest that host genetic background is an important factor in determining whether HTLV-I carriers develop either ATL or HAM/TSP.

We derive the asymptotic power function of the score test for detecting a common relative risk greater than unity from multiple 2 x 2 tables and formulate methods of sample size determination for use when designing stratified prospective studies. The stratified score test is more efficient than the unstratified test when the latter is unbiased.

Statistical methods for testing the null hypothesis of a nonzero difference between two treatments and the sample size determination for matched-pairs studies are investigated. A Wald-type test proposed by Lu and Bean (1995, Statistics in Medicine 14, 1831-1839) is anticonservative, i.e., its false positive error rate is greater than specified. Score method and normal deviate based on a restricted maximum likelihood estimation are presented. These two test statistics are shown to be algebraically equal. Their actual type I error probabilities are satisfactorily close to a nominal level. Numerical examinations demonstrate that the sample size formulas using these alternative methods are reasonable while that by Lu and Bean is not. The efficiency of matching in equivalence studies is positively related to intercorrelation or the kappa coefficient of agreements. We recommend the score or ML methods to establish equivalence of two treatments for individually matched samples.

Human leukocyte antigens (HLAs) play an important role in regulating the immune response to infectious agents and determinants of malignant transformation. We compared the HLA frequencies of 25 black patients with adult T-cell leukemia/lymphoma (ATL) referred to the National Cancer Institute for therapy with a racially similar, asymptomatic control population of human T-cell lymphotrophic virus, type I (HTLV-I)-seropositive individuals (n = 45). Serological typing was performed for MHC class I and II antigens. Antigen frequencies were calculated, and corresponding gene frequencies were estimated using the maximum likelihood method. Comparisons between the ATL and control group were made with chi 2 or Fisher's exact test. Three antigens (A36, B18, and DR53) were found to have a higher frequency in the ATL patients than in the controls (uncorrected two-tailed P < 0.05). The gene frequencies for these antigens also were statistically significant in the uncorrected analysis. However, only A36 approached statistical significance after correction of the P value for multiple comparisons (P = 0.08). The results of this pilot study indicate that black patients with ATL may have increased frequencies of certain class I HLA when compared with a racially similar HTLV-I-positive reference population. This suggests that either these antigens may represent markers for a population at greater risk of developing ATL once infected with HTLV-I or that they were acquired at some point in the process of malignant transformation or progression from the carrier state to onset of ATL. These antigens should be targeted in larger studies to confirm or refute these findings.

Adrenal cancer is a heterogeneous group of neoplasms with unknown etiology. In search of risk factors, we conducted a case-control study based on data from the 1986 National Mortality Followback Survey, which included a questionnaire sent to the next of kin of almost 20,000 deceased adults (age > or = 25 year) in the United States. Information was obtained on a large number of items, including use of cigarettes, alcohol, oral contraceptives (OCs), height and weight and food consumption patterns. A total of 176 subjects who died of adrenal cancer (88 men and 88 women) and 352 controls (176 men and 176 women) who died of causes unrelated to smoking, drinking or OCs (for female controls) were included in the study. Although information on histologic type was not available, most cases were estimated from incidence surveys to be adrenocortical carcinoma, with a small percentage being malignant pheochromocytoma or neuroblastoma. An increased risk was associated with heavy smoking (> or = 25 cigarettes/day) among men (odds ratio [OR] = 2.0, 95% confidence interval [CI] 1.0-4.4) but not women. No clear association was seen for alcohol use, height and weight or food consumption patterns in either sex. Among women, increased risks were found for ever users of OCs (OR = 1.8, 95% CI 1.0-3.2) and especially those who used them before age 25 (OR = 2.5, 95% CI 1.2-5.5). When the analysis was restricted to subjects with spousal respondents, more pronounced risks were seen for ever users of OCs and for those who used OCs before age 25. Our findings suggest that cigarette smoking and use of OCs may increase the risk of adrenal cancer, but additional studies are needed with more detailed information on risk factors and histologic type of adrenal cancer.

The statistical analysis for detecting a seasonal trend in epidemiologic studies has traditionally employed Edwards' method (1961, Annals of Human Genetics 25, 83-85) or a modification (Roger, 1977, Biometrika 64, 152-155) which are formulated under a simple harmonic model with two parameters, amplitude and phase angle. In seasonality studies, researchers usually have known seasons at which peak and trough incidences occur. Utilizing this information, we present the most efficient interval estimation of the ratio of maximum and minimum seasonal frequencies and the uniformly most powerful unbiased test for detecting the seasonal variation using the general theory of Bartlett (1953, Biometrika 40, 12-19). The asymptotic power function and the approximate formula for sample size are derived. A simulation study shows that actual values of power of this score test are satisfactorily close to nominal values even for small samples. The proposed simple score test is more powerful and requires substantially smaller samples for a specific power than the standard Edwards or Roger tests. An alternative method based on the logarithm of the maximum likelihood estimator of the ratio is comparable to the simple score method.

The risk of nasopharyngeal carcinoma (NPC), a relatively rare neoplasm in the United States, was examined in relation to tobacco use in a cohort of nearly 250,000 US veterans whose mortality experience was followed for 26 years. A total of 48 NPC deaths were identified during the follow-up period. Current smokers had a nearly 4-fold increase in risk of NPC compared with non-users of any tobacco, with risk increasing to 6.4 among those smoking more than 2 packs daily. After adjustment for age and number of cigarettes smoked, risks were inversely associated with age at starting to smoke, with the highest risk observed among those who started smoking before age 15, although no clear trend associated with duration of smoking was observed. Former cigarette smokers had a small excess risk of NPC, but no association was detected for cigar/pipe users. This study adds strong evidence to the increasing literature linking cigarette smoking to NPC.

Strata-matched case-control studies based on a given number of cases and k times as many controls are common. We obtain a necessary and sufficient condition for there to exist a numerical solution for k with a desired level of a power. We derive the maximum power of the Cochran test, which may be less than one, when the number of cases is fixed. We provide an approximate formula for the minimum number of cases required for a specified power. There exists a numerical solution (that is, convergence of an iterative method) for k if the number of cases given is greater than this minimum number and no such a solution otherwise. We also show that the incremental gain in relative efficiency of the test with respect to k is diminished as k gets large.

Background: Nasopharyngeal carcinoma (NPC) is a relatively uncommon cancer in the United States. Its etiology among White Americans is not well known, but cigarette smoking has been implicated in some epidemiologic studies., Purpose: The purpose of this study was to investigate the roles of cigarette use and alcohol consumption as risk factors for NPC in the United States., Methods: We conducted a case-control study using data from the National Mortality Followback Survey based on information from death certificates. In this study, we compared use of cigarettes and alcohol by 204 White American men and women who died of NPC with that by 408 who died of causes unrelated to cigarette smoking and alcohol use., Results: Risk of NPC increased in proportion to the amount and duration of smoking (with a more than threefold increase among persons smoking heavily) and declined following cessation of smoking. After controlling for smoking, we found an 80% excess risk of NPC among persons whose intake of alcohol was heavy., Conclusion: Use of cigarettes and consumption of alcohol were found to be statistically significant risk factors for NPC. The findings are among the strongest to date indicating that use of cigarettes and perhaps alcohol may contribute to the etiology of these relatively rare cancers among Whites in the United States.

To evaluate the possibility that genetic factors contribute to the excess rates of multiple myeloma among blacks, serological typing of human leukocyte antigens (HLA) was conducted for black and white male patients and controls who participated in a large population-based case-control interview study. Forty-six black cases, 88 black controls, 85 white cases, and 122 white controls were typed for the Class I antigens (HLA-A, -B, -C) and for the Class II antigens (HLA-DR, HLA-DQ). Black cases had significantly higher gene frequencies than black controls for Bw65, Cw2, and DRw14, while white cases had higher gene frequencies than white controls for A3 and Cw2 and blanks at the DR and DQ loci. Further analysis of the association between Cw2 and multiple myeloma revealed relative risks of 5.7 (95% confidence interval = 1.5-26.6) and 2.6 (95% confidence interval = 1.0-7.2) for blacks and whites, respectively. The frequency of Cw2 in black and white controls was similar. These findings suggest that the Cw2 allele enhances the risk of myeloma in blacks and whites but do not explain the higher incidence of this cancer among blacks. The study also suggests that undefined DQ antigens may play an etiological role, supporting the need for further research into the immunogenetic determinants of myeloma.

We investigate sample size determination for Cochran's test for stratified case-control studies when samples of cases and controls are allocated to maximize the asymptotic efficiency of Cochran's test subject to fixed total cost with cost per control varying by strata. We consider two situations typical of strata-matched case-control studies: when one samples both cases and controls and when cases are given and one samples controls. In each situation we develop and study an asymptotic method for finding the sample size required for a specific power under the optimum allocation proposed by Nam and Fears. Also, for the second situation, we investigate an asymptotic method for determining the common ratio, k, in one-to-k strata-matched case-control studies without cost consideration for a given power. When cases are given, neither the optimum nor the standard control sample sizes appear in a closed form; we present numerical methods for calculating these sample sizes and illustrate them with examples. We find the reduction in total cost obtained under the optimum allocation compared to standard allocation more pronounced as the differences in stratum-specific costs of sampling controls increase.

We investigate the allocation of samples over strata in case-control studies with consideration of sampling costs. We consider two situations, typical of strata-matched case-control studies. Subject to a fixed total cost we derived optimum allocations that maximize the asymptotic efficiency of Cochran's test, that is, minimize the variance of the maximum likelihood estimator of the common odds ratio when the common odds ratio is one. Our results show that the standard design with equal numbers of cases and controls in each stratum is inefficient when costs per control differ greatly from stratum to stratum. We show that the optimum design suggested in this paper is robust for values of the odds ratio common in epidemiologic studies.

Recently, Beal (1987, Biometrics 43, 941-950) found Mee's modification of Anbar's approximate interval estimation for the difference in binomial parameters to be a good choice in small sample sizes. As this method can be derived from the score theory of Bartlett, it is easily corrected for skewness. Exact numerical evaluation shows that this correction is not as important for this case as for the ratio of binomial parameters (Gart and Nam, 1988, Biometrics 44, 323-338). The score theory is also used to extend this method to the stratified or multiple-table case. Thus, good approximate interval estimates for differences, ratios, and odds ratios of binomial parameters can all be derived from the same general theory.

A simple approximate formula for sample sizes for detecting a linear trend in proportions is derived. The formulas for both the uncorrected and corrected Cochran-Armitage test are given. For two binomial proportions these reduce to those given by Casagrande, Pike, and Smith (1978, Biometrics 34, 483-486). Some numerical results of a power study for small sample sizes show that the nominal power corresponding to the approximate sample size is a reasonably good approximation to the actual power.

Stevens suggests a test of fit, based on Bernstein's estimators, of the Hardy-Weinberg law for the ABO system. Nam and Gart extend this test to the generalized ABO-like system and apply it to HLA data. When the recessive gene is rare, Huether and Murphy recall Haldane's point that its Bernstein's estimator is negatively biased and go on to suggest novel corrected versions of it. With the identification of more HLA antigens, it is not uncommon to find, in certain populations, that the sample data contain no double blanks; that is, every individual reacts to at least one antigen for a given locus. Gart and Nam give a simple score test of a zero true recessive-gene frequency for such situations. Here we examine the extended test of Stevens as a test of this hypothesis. We find that it is fully efficient for two codominant alleles but that when the number exceeds two its efficiency may be 50% or lower or as high as 100%, depending on the number of alleles and the pattern of gene frequencies. The tests are applied to a set of HLA data.

A subgroup of 351 subjects with human leukocyte antigen (HLA) typing were available from the Framingham Heart Study for analyses to identify associations with obesity. The subjects consisted of 143 males and 208 females aged 58-88 years at the 15th biennial examination in 1978. The obese classification was based on maximum body mass index (BMI) over the 16 available biennial examinations of the Framingham Heart Study. The subjects were classified as obese if they exceeded the 95th percentile of BMI for 20- to 29-year-old subjects as described in the NHANES II study; males were obese if BMI greater than 31.1 and females were obese if BMI greater than 32.3. There were 27 obese males (18.9%) and 44 obese females (21.2%) in the sample. Gene frequencies were compared between the nonobese and obese groups for the pooled sample as well as by sex. Among alleles previously shown to be related to obesity, HLA Bw35 appeared to be more frequent in obese females but these data did not confirm a difference for the B18 or Cw4 alleles. More importantly, HLA Aw30 was found to be significantly higher among the obese subjects in both males and females. Further analyses adjusting for potential confounding variables reduced the estimated relative risk for obesity for subjects with the Bw35 allele to approximately 1.30 and no longer significant for this sample size. In contrast, the relative risk for Aw30, while reduced, remained significant after adjustment for confounding variables. Based on these data, individuals with the Aw30 allele have a relative risk of 2.61 for obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

In generalized ABO-like genetic systems, particularly for certain human leukocyte antigen (HLA) loci, it is quite likely, even for large sample sizes, that no double recessives (or 'double blanks') may be found. It has been suggested that all such data should be analyzed as if the true recessive gene frequency were 0. We derive an easily computed score [or C(alpha)] statistic which tests for the possibility that, in such instances, this frequency may exceed 0. An associated point estimator is suggested. The methods are applied to the data analyzed by Smouse and Williams (1982, Biometrics 38, 757-768).

Although the simple and adjusted Bernstein's methods are fully efficient for m=2 and m=3 (ABO system) respectively, their efficiency declines for larger values of m. For m greater than or equal to 4, the adjusted or modified Bernstein's method with a single counting iteration leads to a nearly efficient estimator. A single degree of freedom chi-square test of the Hardy-Weinberg law for all m is derived. Some findings on the statistical efficiency of typing various numbers of antigens are given. All the results are illustrated in numerical examples.

Gart and Nam (1984, Biometrics 40, 887-894) consider the analysis of an ABO-like model based on the Hardy-Weinberg law in the commonly occurring case of human leukocyte antigen (HLA) data where there are no double blanks, that is, no recessive homozygotes. They derive a score test, based on the truncated likelihood, of the hypothesis that the true recessive gene (or allele) frequency is zero. Yasuda (1968, Biometrics 24, 915-935) considers a similar codominant system wherein the true recessive gene frequency is assumed zero, but the Hardy-Weinberg law does not hold. In particular, he considers the possibility of a nonzero inbreeding coefficient. We show that the two models are equivalent; each likelihood can be shown to be a reparameterization of the other. Furthermore, the score test of the zero gene frequency in Gart and Nam is identical to the score test for a zero inbreeding coefficient given by Yasuda. The results are applied to an example wherein it appears that the Hardy-Weinberg model is appropriate. Thus, it is not possible in this population to identify homozygous individuals without error from phenotypic data alone.