Faculty Bibliography

For longitudinal binary data with non-monotone non-ignorably missing outcomes over time, a full likelihood approach is complicated algebraically, and with many follow-up times, maximum likelihood estimation can be computationally prohibitive. As alternatives, two pseudo-likelihood approaches have been proposed that use minimal parametric assumptions. One formulation requires specification of the marginal distributions of the outcome and missing data mechanism at each time point, but uses an 'independence working assumption,' i.e. an assumption that observations are independent over time. Another method avoids having to estimate the missing data mechanism by formulating a 'protective estimator.' In simulations, these two estimators can be very inefficient, both for estimating time trends in the first case and for estimating both time-varying and time-stationary effects in the second. In this paper, we propose the use of the optimal weighted combination of these two estimators, and in simulations we show that the optimal weighted combination can be much more efficient than either estimator alone. Finally, the proposed method is used to analyze data from two longitudinal clinical trials of HIV-infected patients.

AIMS: Psoriasis is a common chronic inflammatory T-helper cell-1/17 mediated skin disease. Recent studies suggest that psoriasis, particularly if severe, may be an independent risk factor for atherosclerosis, myocardial infarction (MI), and stroke. We conducted a cohort study using the General Practice Research Database to determine if severe psoriasis patients have an increased risk of cardiovascular (CV) mortality. METHODS AND RESULTS: Severe psoriasis was defined as patients who received a psoriasis diagnosis and systemic therapy consistent with severe psoriasis (n = 3603). Up to four unexposed patients without psoriasis were selected from the same practices and start dates for each psoriasis patient (n = 14 330). For every death, the cause was determined by review of the electronic medical record. Severe psoriasis was an independent risk factor for CV mortality (HR 1.57; 95% CI 1.26, 1.96) when adjusting for age, sex, smoking, diabetes, hypertension, and hyperlipidaemia. Overall, severe psoriasis patients experienced one extra CV death per 283 patients per year, even when adjusting for major CV risk factors. The relative risk of CV mortality was modified by age. For example, the RR of CV death for a 40-year-old and 60-year-old with severe psoriasis was 2.69 (1.45, 4.99) and 1.92 (1.41, 2.62), respectively. The findings were robust to multiple sensitivity analyses. CONCLUSION: Patients with severe psoriasis have an increased risk of CV mortality that is independent of traditional CV risk factors. Additional studies are needed to determine the mechanism of this association and the impact that control of psoriasis has on CV risk

BACKGROUND/AIM: Cyclin D1 is a mediator of cell-cycle control that is frequently overexpressed in primary ductal breast carcinomas, but its role is controversial. A polymorphism in the CCND1 gene, G870A, results in an aberrantly spliced protein (cyclin D1b) lacking the Thr-286 phosphorylation site necessary for nuclear export. Studies of murine fibroblasts have shown that although overexpression of canonical cyclin D1 (cyclin D1a) alone is not sufficient to drive malignant transformation, expression of nuclear cyclin D1b is oncogenic. Our objectives were to determine whether cyclin D1b is expressed in human breast carcinomas and to characterize the relationship of this protein to both cyclin D1a and clinical outcome in breast cancer patients. PATIENTS AND METHODS: We performed a prospective cohort study of women with early-stage breast cancer and analyzed cyclin D1a and D1b expression in primary breast tumor sections. Expression was tested for correlation with other breast cancer prognostic factors and clinical outcome, including recurrence or death. RESULTS: A total of 118 patients were included in this analysis, with a median follow-up of 44 months. Cyclin D1b was expressed in 26% of tumors and cyclin D1a was overexpressed in 27%; co-expression occurred in 4%. Cyclin D1a and/or D1b expression were not significantly associated with estrogen or progesterone receptor negativity, Her2 overexpression, young age, lymph node positivity, high tumor grade, nor large tumor size. The risk of recurrence was higher in those co-expressing D1a and D1b compared to the expression of either alone (relative risk=5.3, 95% confidence interval 1.27 to 22.1, p=0.02). The hazard ratio for those with co-expression compared with those without was 6.05 (p=0.04). CONCLUSION: Expression of cyclin D1b occurs in primary human breast carcinomas and its coexpression with cyclin D1a may be a marker for increased recurrence risk, independently of other factors.

BACKGROUND: The development of a simple, reliable, valid and responsive method for measuring the extent of skin involvement in psoriasis is important for use in epidemiological studies. OBJECTIVES: We sought to investigate the psychometric characteristics of the Patient Report of Extent of Psoriasis Involvement (PREPI), a single-question method for measuring body surface area affected by psoriasis. METHODS: This was a cross-sectional study of 140 patients with psoriasis, with an exploratory prospective longitudinal cohort component. Reliability was measured via a test-retest approach and criterion validity was investigated by comparing the PREPI with an assessment of body surface area of involvement by a dermatologist. We additionally compared Skindex-29 scores with the PREPI. To demonstrate responsiveness and establish a minimally important difference in the PREPI, we created receiver operating characteristic curves for the PREPI instrument. RESULTS: The test-retest reliability of the PREPI was nearly perfect [intraclass correlation coefficient (ICC) = 0.99, 95% confidence interval (CI) 0.97-0.99], and there was substantial agreement between patient and physician assessments (ICC = 0.82, 95% CI 0.75-0.87). The PREPI showed significant correlations with all Skindex-29 domains. We found the PREPI to be responsive to change and identified changes in the PREPI score that have good discrimination between patients with and without a minimally important clinical difference. CONCLUSIONS: Our study suggests that the PREPI is a reliable, valid and responsive measure of body surface area affected by psoriasis that may be useful for future epidemiological research.

BACKGROUND: Validated outcome measures in dermatology help standardize and improve patient care. A scoring system of skin disease severity in dermatomyositis known as the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) has been developed. OBJECTIVES: To simplify and improve the tool for clinical research and care, we modified the CDASI and validated the new version, v2. METHODS: The original CDASI has four activity and two damage measures. The modified CDASI has three activity and two damage measures. The skin disease of 20 patients with dermatomyositis was evaluated by the same dermatologist using both the original and the modified CDASI. Global validation measures were implemented to assess overall skin disease state, skin disease activity and skin damage. Spearman's rho (r(sp)), adjusted for multiple observations on subjects, was used to determine the relationship between the two versions of the CDASI and their correlation with the physician global measures (PGMs). RESULTS: The total score and activity and damage subscores of the original and the modified CDASI correlated perfectly with each other (r(sp) = 0.99, 1.00, 1.00). The PGM-overall skin scale correlated with the total scores (r(sp) = 0.72, r(sp) = 0.76) and activity subscores (r(sp) = 0.68, r(sp) = 0.63) but not with the damage subscores (r(sp) = 0.14, r(sp) = 0.15) of the original and the modified CDASI, respectively. However, the PGM-activity and PGM-damage scales correlated with the activity (r(sp) = 0.76, r(sp) = 0.75) and damage subscores (r(sp) = 0.90, r(sp) = 0.90), respectively, of the original and the modified CDASI. CONCLUSIONS: The modified CDASI is perfectly correlated with the original CDASI. It has equally good concurrent validity with the PGM-overall skin and PGM-activity scales. The CDASI subscores have equally good concurrent validity with the PGM-activity and PGM-damage scales. We suggest that PGMs of skin disease activity and damage should be assessed separately for greater specificity. The modified CDASI is a refined and equally as useful outcome measure.

Lymphedema is one of many arm problems reported by breast cancer survivors. Understanding the impact of lymphedema on quality of life requires consideration that arm symptoms may occur with or without lymphedema. It was hypothesized that specific arm symptoms and pain, related or unrelated to lymphedema, would be more associated with quality of life outcomes than arm swelling. The relation of arm swelling and of arm symptoms and associated severity with a range of quality of life outcomes following breast cancer treatment was assessed in a diverse sample of 295 women, 141 of whom had a clinical diagnosis of lymphedema. Arm swelling (as defined by interlimb volume or circumference differences) and lymphedema severity (defined by Common Toxicity Criteria) were less correlated with quality of life than total number of arm symptoms and specific individual symptoms. Pain in the affected arm correlated with poor quality of life outcomes, regardless of arm swelling. When evaluating the impact of lymphedema on quality of life, arm swelling may not be as important as the total number and specific types of arm symptoms present, as these may be more informative about quality of life outcomes in survivors of breast cancer with and without lymphedema.

BACKGROUND: Differences in risk factors for metastases at different time intervals after treatment have been described in several malignancies; however, to the authors' knowledge, no extensive study examining this issue in melanoma has been conducted to date. METHODS: The authors performed a nested case-control study of patients with melanoma who presented with only local disease. Patients in the case group included 549 patients who developed metastases > or =6 months after surgery. Of these, 320 patients developed metastasis within 3 years after undergoing definitive surgery (early metastases [EM]), and 70 patients developed metastasis > or =8 years after undergoing definitive surgery (late metastases [LM]). For each case, a control patient was chosen who had melanoma but who did not develop metastases in the same interval. Univariate and conditional multivariate logistic regression were used in the analysis of 34 clinical and tumor characteristics. RESULTS: Multivariate analysis confirmed previously established risk factors for metastases, such as increasing tumor thickness. In addition, the authors discovered that a personal history of nonmelanoma skin cancer (P = .006) and a history of cancer other than skin cancer (P = .020) also were associated with metastasis. In comparing the 320 EM patients with the 70 LM patients, EM patients were more likely to have thicker lesions (P < .001), ulcerated lesions (P = .016), and a history of nonmelanoma skin cancer (P = .024). CONCLUSIONS: In this study, 2 potentially novel risk factors for melanoma metastases were identified, and different profiles of risk factors were constructed for EM versus LM. These differences may be important in future risk identification and stratification for clinical trials and for the management and treatment of patients with melanoma.

OBJECTIVES: The severity of acute carbon monoxide (CO) poisoning is often based on non-specific clinical criteria because there are no reliable laboratory markers. We hypothesized that a pattern of plasma protein values might objectively discern CO poisoning severity. This was a pilot study to evaluate protein profiles in plasma samples collected from patients at the time of initial hospital evaluation. The goal was to assess whether any values differed from age- and sex-matched controls using a commercially available plasma screening package. METHODS: Frozen samples from 63 suspected CO poisoning patients categorized based on clinical signs, symptoms, and blood carboxyhemoglobin level were analyzed along with 42 age- and sex-matched controls using Luminex-based technology to determine the concentration of 180 proteins. RESULTS: Significant differences from control values were found for 99 proteins in at least one of five CO poisoning groups. A complex pattern of elevations in acute phase reactants and proteins associated with inflammatory responses including chemokines/cytokines and interleukins, growth factors, hormones, and an array of auto-antibodies was found. Fourteen protein values were significantly different from control in all CO groups, including patients with nominal carboxyhemoglobin elevations and relatively brief intervals of exposure. CONCLUSIONS: The data demonstrate the complexity of CO pathophysiology and support a view that exposure causes acute inflammatory events in humans. This pilot study has insufficient power to discern reliable differences among patients who develop neurological sequelae but future trials are warranted to determine whether plasma profiles predict mortality and morbidity risks of CO poisoning.

BACKGROUND: Limited empirical data are available on the effects of genetic counseling and testing among African American women. OBJECTIVE: To evaluate the effects of genetic counseling and testing in African American women based on different levels of exposure: (a) women who were randomized to culturally tailored (CTGC) and standard genetic counseling (SGC) to women who declined randomization (non-randomized group), (b) participants and non-participants in genetic counseling, and (c) BRCA1 and BRCA2 (BRCA1/2) test result acceptors and decliners. DESIGN: Randomized trial of genetic counseling conducted from February 2003 to November 2006. MEASURES: We evaluated changes in perceived risk of developing breast cancer and cancer worry. RESULTS: Women randomized to CTGC and SGC did not differ in terms of changes in risk perception and cancer worry compared to decliners. However, counseling participants had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (p = 0.03). Test result acceptors also had a significantly greater likelihood of reporting decreases in cancer worry (p = 0.03). However, having a cancer history (p = 0.03) and a BRCA1/2 prior probability (p = 0.04) were associated with increases in cancer worry. CONCLUSIONS: Although CTGC did not lead to significant improvements in perceived risk or psychological functioning, African American women may benefit from genetic counseling and testing. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease. But, follow-up support may be needed for women who have a personal history of cancer and those with a greater prior probability of having a BRCA1/2 mutation.

PURPOSE: The combination of the oral alkylating agent temozolomide and the oral multikinase inhibitor sorafenib was evaluated in advanced melanoma patients. EXPERIMENTAL DESIGN: Patients with metastatic melanoma (n = 167) were treated on four arms. All patients received sorafenib at 400 mg p.o. twice daily without interruption. Patients without brain metastases or prior temozolomide were randomized between arm A: extended dosing of temozolomide (75 mg/m(2) temozolomide daily for 6 of every 8 weeks) and arm B: standard dosing (150 mg/m(2) temozolomide daily for 5 of every 28 days). Patients previously treated with temozolomide were enrolled on arm C: extended dosing of temozolomide. Patients with brain metastases and no prior temozolomide were assigned to arm D: standard dosing. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included response rate, toxicity rates, and the rates of BRAF or NRAS mutations. RESULTS: The 6-month PFS rate for arms A, B, C, and D were 50%, 40%, 11%, and 23%. The median PFS for patients on arm A, B, C, and D was 5.9, 4.2, 2.2, and 3.5 months, respectively. No significant differences were observed between arms A and B in 6-month PFS rate, median PFS, or response rates. Treatment was well tolerated in all arms. No significant differences in toxicity were observed between arms A and B except for more grade 3 to 4 lymphopenia in arm A. CONCLUSION: Temozolomide plus sorafenib was well tolerated and showed activity in melanoma patients without prior history of temozolomide. The activity of this combination regimen warrants further investigation. (Clin Cancer Res 2009;15(24):7711-8).