Bahjat F. Qaqish

An R2 statistic for fixed effects in the linear mixed model

Statisticians most often use the linear mixed model to analyze Gaussian longitudinal data. The value and familiarity of the R(2) statistic in the linear univariate model naturally creates great interest in extending it to the linear mixed model. We define and describe how to compute a model R(2) statistic for the linear mixed model by using only a single model. The proposed R(2) statistic measures multivariate association between the repeated outcomes and the fixed effects in the linear mixed model. The R(2) statistic arises as a 1-1 function of an appropriate F statistic for testing all fixed effects (except typically the intercept) in a full model. The statistic compares the full model with a null model with all fixed effects deleted (except typically the intercept) while retaining exactly the same covariance structure. Furthermore, the R(2) statistic leads immediately to a natural definition of a partial R(2) statistic. A mixed model in which ethnicity gives a very small p-value as a longitudinal predictor of blood pressure (BP) compellingly illustrates the value of the statistic. In sharp contrast to the extreme p-value, a very small R(2) , a measure of statistical and scientific importance, indicates that ethnicity has an almost negligible association with the repeated BP outcomes for the study.

Hepatitis B and Hepatitis C in Emergency Department Patients

BACKGROUND Infections with hepatitis B virus (HBV), hepatitis C virus (HCV), and the human immunodeficiency virus type 1 (HIV-1) are common in inner-city populations, but their frequency and interrelations are not well established. METHODS During a six-week period, excess serum samples were collected, along with information on risk factors, from all adult patients presenting to an inner-city emergency department. The samples were assayed for hepatitis B surface antigen (HBsAg) and antibodies to HCV and HIV-1. RESULTS Of the 2523 patients tested, 612 (24 percent) were infected with at least one of the three viruses. Five percent were seropositive for HBV, 18 percent for HCV, and 6 percent for HIV-1. HCV was found in 145 of the 175 intravenous drug users (83 percent), 36 of the 171 transfusion recipients (21 percent), and 5 of the 24 homosexual men (21 percent). Among black men 35 to 44 years of age, the seroprevalence of HCV was 51 percent. HBsAg was present in 9 percent of those whose only identifiable risk was possible heterosexual exposure. At least one viral marker was found in about 30 percent of the patients who were actively bleeding or in whom procedures were performed. Testing for HIV-1 alone would have failed to identify 87 percent of the patients infected with HBV and 80 percent of those infected with HCV. CONCLUSIONS In a population of patients in an inner-city emergency room, HBV, HCV, and HIV-1 are all highly prevalent. However, routine screening for HIV-1 alone would identify only a small fraction of the patients who pose risks of severe viral infections, including HBV and HCV, to providers.

Concurrent radiation therapy and chemotherapy followed by esophagectomy for localized esophageal carcinoma.

PURPOSE A prospective study was performed to determine the outcome of patients with esophageal cancer who received preoperative radiation therapy and chemotherapy followed by esophagectomy, and to determine the role of preresection esophagogastroduodenoscopy (EGD) in predicting the patients in whom surgery could possibly be omitted, and the impact of surgery on survival. MATERIALS AND METHODS Thirty-five patients with localized carcinoma of the esophagus received concurrent external-beam radiotherapy and chemotherapy followed by esophagectomy. Patients received 45 Gy in 25 fractions. Chemotherapy consisted of continuous infusion fluorouracil (5-FU; 1,000 mg/m2/d) on days 1 through 4 and 29 through 32 and cisplatin (100 mg/m2) on day 1. Patients underwent an Ivor-Lewis esophagectomy 18 to 33 days after completion of radiotherapy. RESULTS Eighty percent of the patients had squamous cell carcinoma and 20% had adenocarcinoma. In addition, 51% had a pathologic complete response (CR). Twenty-two of the 35 underwent a preresection EGD before resection. Seventeen of the 22 (77%) had negative pathology from the preresection EGD, but seven of the 17 (41%) had residual tumor at surgery. The median survival and disease-free survival rates for all patients were 25.8 months and 32.8 months, respectively. Eighteen patients (51%) had no tumor at resection. The median survival for these patients was 36.8 months; the median disease-free survival time has not been reached. The median survival and disease-free survival rate for the patients with residual tumor in the surgical specimen were 12.9 months and 10.8 months, respectively. CONCLUSION Preresection EGD is not reliable for determining the presence of residual disease or the patients in whom surgery could be omitted. Twenty-five percent of the patients with residual tumor in the resected surgical specimen were long-term survivors; this suggests a benefit from esophagectomy after concurrent radiotherapy and chemotherapy.

Increasing Use of Mammography Among Older, Rural African American Women: Results From a Community Trial

OBJECTIVES A community trial was undertaken to evaluate the effectiveness of the North Carolina Breast Cancer Screening Program, a lay health advisor network intervention intended to increase screening among rural African American women 50 years and older. METHODS A stratified random sample of 801 African American women completed baseline (1993-1994) and follow-up (1996-1997) surveys. The primary outcome was self-reported mammography use in the previous 2 years. RESULTS The intervention was associated with an overall 6 percentage point increase (95% confidence interval [CI] = -1, 14) in community-wide mammography use. Low-income women in intervention counties showed an 11 percentage point increase (95% CI = 2, 21) in use above that exhibited by low-income women in comparison counties. Adjustment for potentially confounding characteristics did not change the results. CONCLUSIONS A lay health advisor intervention appears to be an effective public health approach to increasing use of screening mammography among low-income, rural populations.

The Carolina Breast Cancer Study: integrating population-based epidemiology and molecular biology

SummaryThe integration of epidemiology and molecular biology provides a new strategy to identify additional risk factors for breast cancer and to better understand the role played by traditionally recognized risk factors. The Carolina Breast Cancer Study (CBCS) is a population-based, case-control study designed to identify causes of breast cancer among Caucasian and African-American women who are residents of a 24-county area of central and eastern North Carolina. Information on established and potential breast cancer risk factors is obtained by personal interviews. Blood samples are collected from all consenting participants. Medical record documentation and paraffin-embedded tumor specimens are obtained for all breast cancer patients. DNA from tumor tissue is tested for a variety of molecular alterations characteristic of breast cancer. Germline DNA from blood lymphocytes is evaluated for presence of alleles increasing susceptibility to breast cancer. Statistical analyses evaluate gene-environment interaction by exploring the associations between environmental/behavioral factors and breast cancer in relation to specific molecular alterations (germline and tumor). Results will help identify high-risk women, clarify causal pathways, and hopefully contribute to the prevention of breast cancer.

Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia

RATIONALE Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized. OBJECTIVES To use a standard protocol for measuring nNO to establish a disease-specific cutoff value at one site, and then validate at six other sites. METHODS At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD. MEASUREMENTS AND MAIN RESULTS At the lead site, nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5-867.0 nl/min), asthma (267.8 ± 103.2; 125.0-589.7 nl/min), or chronic obstructive pulmonary disease (223.7 ± 87.1; 109.7-449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6-386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD. CONCLUSIONS Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.

Marginal models for correlated binary responses with multiple classes and multiple levels of nesting

A model for correlated binary data is presented. Marginal probabilities and odds ratios are allowed to have general regression structures that include multiple classes and multiple levels of nesting. Estimation is done through the generalized estimating equations approach of Liang and Zeger (1986, Biometrika 73, 13-22). They are contrasted with conditional models and recommendations for choosing between the two are given. Examples from genetic epidemiology are presented.

The associations of adolescent cigarette smoking, alcoholic beverage consumption, environmental tobacco smoke, and ionizing radiation with subsequent breast cancer risk (United States)

AbstractObjectives: Studies of breast cancer among survivors of the World War II atomic bomb blasts over Japan suggest that the adolescent breast may be particularly sensitive to carcinogenic insult. To further explore that possibility we examined the relationships of cigarette smoking, alcohol consumption, environmental tobacco smoke (ETS) exposure, and medical treatment with ionizing radiation during adolescence with subsequent breast cancer risk. Methods: Data from the Carolina Breast Cancer Study, a population-based, case–control study of breast cancer in North Carolina women aged 20–74years (864 cases, 790 controls), were analyzed. Results: A modest increase in breast cancer risk was suggested for women who began to smoke cigarettes between the ages of 10 and 14 years (OR: 1.5, CI: 0.9–2.5), and for women exposed to ionizing radiation between ages 10 and 19 years to treat or monitor a medical condition (OR: 1.6, CI: 0.5–2.5). Neither exposure to ETS at home prior to age 18 years (OR: 1.1, CI: 0.9–1.3) nor initiation of alcoholic beverage consumption between ages 10 and 15 years (OR: 1.1, CI: 0.6–1.8) appeared to increase risk. Conclusions: Our results are consistent with previous evidence suggesting that some adolescent exposures could influence future breast cancer risk.

Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

PURPOSE To perform a prospective, multi-institutional, phase 2 study of a substantial decrease in concurrent chemoradiation therapy (CRT) intensity as primary treatment for favorable-risk, human papillomavirus-associated oropharyngeal squamous cell carcinoma. METHODS AND MATERIALS The major inclusion criteria were: (1) T0 to T3, N0 to N2c, M0; (2) human papillomavirus or p16 positive; and (3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatinum (30 mg/m(2)). The primary study endpoint was pathologic complete response (pCR) rate based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Power computations were performed for the null hypothesis that the pCR rate is 87% and n=40, resulting in a type 1 error of 14.2%. Secondary endpoint measures included physician-reported toxicity (Common Toxicity Terminology for Adverse Events, CTCAE), patient-reported symptoms (PRO-CTCAE), and modified barium swallow studies. RESULTS The study population was 43 patients. The pCR rate was 86% (37 of 43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very severe symptoms was as follows: mucositis 34%/45%, general pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55%, and xerostomia 2%/75%. Grade 3/4 hematologic toxicities were 11%. Thirty-nine percent of patients required a feeding tube for a median of 15 weeks (range, 5-22 weeks). There were no significant differences in modified barium swallow studies before and after CRT. CONCLUSIONS The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatinum is very high in favorable-risk oropharyngeal squamous cell carcinoma, with evidence of decreased toxicity compared with standard therapies. ClinicalTrials.gov ID: NCT01530997.

Using an Office System Intervention to Increase Breast Cancer Screening

AbstractOBJECTIVE: To evaluate an innovative approach to continuing medical education, an outreach intervention designed to improve performance rates of breast cancer screening through implementation of office systems in community primary care practices. DESIGN: Randomized, controlled trial with primary care practices assigned to either the intervention group or control group, with the practice as the unit of analysis. SETTING: Twenty mostly rural counties in North Carolina. PARTICIPANTS: Physicians and staff of 62 randomly selected family medicine and general internal medicine practices, primarily fee-for-service, half group practices and half solo practitioners. INTERVENTION: Physician investigators and facilitators met with practice physicians and staff over a period of 12 to 18 months to provide feedback on breast cancer screening performance, and to assist these primary care practices in developing office systems tailored to increase breast cancer screening. MEASUREMENTS AND MAIN RESULTS: Physician questionnaires were obtained at baseline and follow-up to assess the presence of five indicators of an office system. Three of the five indicators of office systems increased significantly more in intervention practices than in control practices, but the mean number of indicators in intervention practices at follow-up was only 2.8 out of 5. Cross-sectional reviews of randomly chosen medical records of eligible women patients aged 50 years and over were done at baseline (n=2,887) and follow-up (n=2,874) to determine whether clinical breast examinations and mammography, were performed. Results for mammography were recorded in two ways, mention of the test in the visit note and actual report of the test in the medical record. These reviews showed an increase from 39% to 51% in mention of mammography in intervention practices, compared with an increase from 41% to 44% in control practices (p=.01). There was no significant difference, however, between the two groups in change in mammograms reported (intervention group increased from 28% to 32.7%; control group increased from 30.6% to 34.0%, p=.56). There was a nonsignificant trend (p=.06) toward a greater increase in performance of clinical breast examination in intervention versus control practices. CONCLUSIONS: A moderately intensive outreach intervention to increase rates of breast cancer screening through the development of office systems was modestly successful in increasing indicators of office systems and in documenting mention of mammography, but had little impact on actual performance of breast cancer screening. At follow-up, few practices had a complete office system for breast cancer screening. Outreach approaches to assist primary care practices implement office systems are promising but need further development.