Confidence-interval construction for rate ratio in matched-pair studies with incomplete data

Matched-pair design is often used in clinical trials to increase the efficiency of establishing equivalence between two treatments with binary outcomes. In this article, we consider such a design based on rate ratio in the presence of incomplete data. The rate ratio is one of the most frequently used indices in comparing efficiency of two treatments in clinical trials. In this article, we propose 10 confidence-interval estimators for the rate ratio in incomplete matched-pair designs. A hybrid method that recovers variance estimates required for the rate ratio from the confidence limits for single proportions is proposed. It is noteworthy that confidence intervals based on this hybrid method have closed-form solution. The performance of the proposed confidence intervals is evaluated with respect to their exact coverage probability, expected confidence interval width, and distal and mesial noncoverage probability. The results show that the hybrid Agresti–Coull confidence interval based on Fieller’s theorem performs satisfactorily for small to moderate sample sizes. Two real examples from clinical trials are used to illustrate the proposed confidence intervals.postprin

Use of the International Prostate Symptom Score (IPSS) in Chinese male patients with benign prostatic hyperplasia

Purpose: To test the psychometric properties of the International Prostate Symptom Score (Hong Kong Chinese version 2) (IPSS) in Chinese male patients with benign prostatic hyperplasia (BPH) under secondary care. Methods: A prospective longitudinal study was done by interviewing subjects at baseline, at 2 week after baseline for assessing test–retest reliability and at 26 week after baseline for assessing responsiveness. All subjects were interviewed to complete a structured questionnaire including IPSS, Short Form-12 Health Survey version 2 (SF-12v2) and Depression Anxiety Stress Scale (DASS). Results: The IPSS HRQOL score had weak correlations with SF-12v2 summary and DASS domain scores. For reliability analysis, Cronbach’s alpha coefficient was 0.90 for the seven symptom-related items. The intraclass correlation coefficients of the IPSS total symptom score and HRQOL score were 0.90 and 0.86, respectively. For sensitivity, statistically significant differences were detected between the subjects with BPH and those without for IPSS total symptom score (effect size=0.68) but not the IPSS HRQOL score. The areas under ROC curves for the IPSS total symptom and HRQOL scores were 0.67 and 0.60, respectively. Conclusions: The IPSS was valid, reliable instrument in Chinese patients with BPH. The IPSS total symptom score, but not the HRQOL score, is sensitive in differentiating subgroups

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16–23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrolment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy=100%; 95% CI:12–100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts

On Confidence Interval Construction for Establishing Equivalence of Two Binary-Outcome Treatments in Matched-Pair Studies in the Presence of Incomplete Data

Matched-pair design is often adopted in equivalence or non-inferiority trials to increase the efficiency of binary-outcome treatment comparison. Briefly, subjects are required to participate in two binary-outcome treatments (e. g., old and new treatments via crossover design) under study. To establish the equivalence between the two treatments at the α significance level, a (1-α)100% confidence interval for the correlated proportion difference is constructed and determined if it is entirely lying in the interval (-δ 0,δ 0) for some clinically acceptable threshold δ 0 (e. g., 0.05). Nonetheless, some subjects may not be able to go through both treatments in practice and incomplete data thus arise. In this article, a hybrid method for confidence interval construction for correlated rate difference is proposed to establish equivalence between two treatments in matched-pair studies in the presence of incomplete data. The basic idea is to recover variance estimates from readily available confidence limits for single parameters. We compare the hybrid Agresti-Coull, Wilson score and Jeffreys confidence intervals with the asymptotic Wald and score confidence intervals with respect to their empirical coverage probabilities, expected confidence widths, ratios of left non-coverage probability, and total non-coverage probability. Our simulation studies suggest that the Agresti-Coull hybrid confidence intervals is better than the score-test-based and likelihood-ratio-based confidence interval in small to moderate sample sizes in the sense that the hybrid confidence interval controls its true coverage probabilities around the pre-assigned coverage level well and yield shorter expected confidence widths. A real medical equivalence trial with incomplete data is used to illustrate the proposed methodologies. © 2011 International Chinese Statistical Association.link_to_subscribed_fulltex

A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-03-23T17:00:50Z No. of bitstreams: 1 Joura EA A 9-valent....pdf: 459983 bytes, checksum: e7a12c9084a672048403e87b557da624 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-03-23T18:18:32Z (GMT) No. of bitstreams: 1 Joura EA A 9-valent....pdf: 459983 bytes, checksum: e7a12c9084a672048403e87b557da624 (MD5)Made available in DSpace on 2016-03-23T18:18:32Z (GMT). No. of bitstreams: 1 Joura EA A 9-valent....pdf: 459983 bytes, checksum: e7a12c9084a672048403e87b557da624 (MD5) Previous issue date: 2015The Medical University of Vienna. Comprehensive Cancer Center. Vienna.Moffitt Cancer Center. Tampa, Florida, USA.University of Bergen–Haukeland University Hospital. Department of Clinical Medicine. Bergen, Norway.Université Laval. Québec, Canadá.University of Washington. Seattle, USA.University of Copenhagen. Coordinating Research Center. Frederiksberg Hospital. Copenhagen.Associação Obras Sociais Irmã Dulce. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.University of Hong Kong. Hong Kong.Aarhus University Hospital. Department of Obstetrics and Gynecology. Aarhus, Denmark.Instituto Nacional de Salud Pública. Cuernavaca, Morelos, Mexico.Mahidol University. Faculty of Tropical Medicine. Nakhon Pathom, Thailand.Investigación Clínica. Medellín, Colombia.University of British Columbia. Vancouver, Canada.University Medical Center Hamburg–Eppendorf. Department of Gynecology. Hamburg, Germany.Mackay Memorial Hospital. Taipei, Taiwan.Wolfson Institute of Preventive Medicine. London.Royal Women’s Hospital. University of Melbourne and Murdoch Childrens Research Institute. Parkville, VIC, Australia.University of Alabama. Division of Gynecologic Oncology. Birmingham.Danish Cancer Society Research Center and Department of Gynecology. Rigshospitalet, Copenhagen.University of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJ, USA.University of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJ, USA.University of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJ, USA.University of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJ, USA.University of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJ, USA.University of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJ, USA.University of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJUniversity of Alabama. Division of Gynecologic Oncology. Birmingham / Merck, Whitehouse Station, NJ, USA.Broad Spectrum HPV Vaccine Study.BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine