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A cause-specific cumulative incidence function (CIF) is the probability of failure from a specific cause as a function of time. In randomized trials, a difference of cause-specific CIFs (treatment minus control) represents a treatment effect. Cause-specific CIF in each intervention arm can be estimated based on the usual non-parametric Aalen-Johansen estimator which generalizes the Kaplan-Meier estimator of CIF in the presence of competing risks. Under random censoring, asymptotically valid Wald-type confidence intervals (CIs) for a difference of cause-specific CIFs at a specific time point can be constructed using one of the published variance estimators. Unfortunately, these intervals can suffer from substantial under-coverage when the outcome of interest is a rare event, as may be the case for example in the analysis of uncommon adverse events. We propose two new approximate interval estimators for a difference of cause-specific CIFs estimated in the presence of competing risks and random censoring. Theoretical analysis and simulations indicate that the new interval estimators are superior to the Wald CIs in the sense of avoiding substantial under-coverage with rare events, while being equivalent to the Wald CIs asymptotically. In the absence of censoring, one of the two proposed interval estimators reduces to the well-known Agresti-Caffo CI for a difference of two binomial parameters. The new methods can be easily implemented with any software package producing point and variance estimates for the Aalen-Johansen estimator, as illustrated in a real data example.

Compassionate use (CU) is a treatment option for patients with serious or life-threatening medical conditions that provides access to locally unlicensed medications (generally free of charge) when all available treatment options have been exhausted and enrollment in a clinical trial is not possible.To examine the disparity in CU access observed across countries and explore the key driving factors.This study analyzed all Novartis CU requests (for individual/named patients and cohort programs) received between January 1, 2018, and December 31, 2020, and investigated selected country-specific factors for association with request activity. Data analysis was performed from February 2021 to February 2022.Country-specific request activity was quantified using request counts and rates per million population and examined in stratified and multivariable analyses (negative-binomial regression) for association with the following covariates: existence of local CU regulations and their public availability, clinical trial activity, population size, and gross domestic product.During the 36-month observation period, 31 711 CU requests were received from 110 countries, 23 194 (73%) of which came from only 10 high-income countries. All high-income countries combined accounted for 27 612 (87%) of all requests, while lower-middle-income and low-income countries contributed only 1021 (3%). Of all requests, 29 870 (94%) were from countries with CU regulations made publicly available on the internet, and higher request activity was demonstrated in countries conducting more clinical trials. Presence and public availability of CU regulations, population size, gross domestic product, and clinical trial activity were independently associated with the CU request activity in multivariable analysis.In this cohort study analyzing Novartis CU requests over a 3-year period, existence and public availability of CU regulations and local clinical trial activity were positively associated with higher CU request rates. The analysis also identified an association between macroeconomic factors and CU request activity, despite the generally free provision of unlicensed therapeutic products. Similar analyses of other comparable experiences are needed to supplement these initial observations. Ultimately, better understanding of factors associated with CU request activity would translate into improved early access to novel lifesaving products for patients with unmet medical needs around the world.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler

Background One factor many women consider when choosing a medical specialty is the plan to have children and the compatibility of their chosen specialty with motherhood. Objective We surveyed Hispanic female physicians who are mothers to collect demographic information, specialty choice, childbearing, and professional and personal life characteristics, along with respondents' suggestions for female physicians who want to start a family, and how hospitals and medical institutions could enhance their support of female medical staff members with children. Methods The questionnaire was fielded on an online forum for Hispanic female physicians who are mothers. We summarized data by frequency and percentages, and means and standard deviations. Results Common medical specialties of respondents included pediatrics, family medicine, and obstetrics and gynecology, and 19% did not report a medical specialty. Most respondents were married (72%), had 1 or 2 children (89%), and worked at a public hospital 5 days a week (51%). Forty-four percent reported they slept 6 or more hours a night. Differences among specialties included dermatologists, radiologists, and gynecologists reporting working more than other specialties (6 to 7 days a week), psychiatrists reporting greater use of psychiatric medications, and anesthesiologists reporting lower rates of marriage. Female surgeons and emergency medicine physicians reported the highest consumption of alcohol. Conclusions The results offer initial insights into how medical specialty choice may affect female physicians' work-life balance and can be used to provide guidance to female learners who plan to have a family.

Exposure-adjusted event rate is a quantity often used in clinical trials to describe average event count per unit of person-time. The event count may represent the number of patients experiencing first (incident) event episode, or the total number of event episodes, including recurring events. For inference about difference in the exposure-adjusted rates between interventions, many methods of interval estimation rely on the assumption of Poisson distribution for the event counts. These intervals may suffer from substantial undercoverage both, asymptotically due to extra-Poisson variation, and in the settings with rare events even when the Poisson assumption is satisfied. We review asymptotically robust methods of interval estimation for the rate difference that do not depend on distributional assumptions for the event counts, and propose a modification of one of these methods. The new interval estimator has asymptotically nominal coverage for the rate difference with an arbitrary distribution of event counts, and good finite sample properties, avoiding substantial undercoverage with small samples, rare events, or over-dispersed data. The proposed method can handle covariate adjustment and can be implemented with commonly available software. The method is illustrated using real data on adverse events in a clinical trial.

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY).METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison.RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%).CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.

In power analysis for multivariable Cox regression models, variance of the estimated log-hazard ratio for the treatment effect is usually approximated by inverting the expected null information matrix. Because, in many typical power analysis settings, assumed true values of the hazard ratios are not necessarily close to unity, the accuracy of this approximation is not theoretically guaranteed. To address this problem, the null variance expression in power calculations can be replaced with one of the alternative expressions derived under the assumed true value of the hazard ratio for the treatment effect. This approach is explored analytically and by simulations in the present paper. We consider several alternative variance expressions and compare their performance to that of the traditional null variance expression. Theoretical analysis and simulations demonstrate that, whereas the null variance expression performs well in many nonnull settings, it can also be very inaccurate, substantially underestimating, or overestimating the true variance in a wide range of realistic scenarios, particularly those where the numbers of treated and control subjects are very different and the true hazard ratio is not close to one. The alternative variance expressions have much better theoretical properties, confirmed in simulations. The most accurate of these expressions has a relatively simple form. It is the sum of inverse expected event counts under treatment and under control scaled up by a variance inflation factor.

Background In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) reduced the risk of renal dysfunction compared with radical nephrectomy (RN); however, overall survival was better in the RN arm. Objective To determine whether treatment effect on the risk of renal dysfunction and all-cause mortality differed in magnitude across levels of baseline variables. Design, setting, and participants This was an exploratory subgroup analysis of EORTC 30904, a phase 3 randomized trial conducted in patients with a small (≤5cm) renal mass and normal contralateral kidney. Intervention Patients were randomized to RN ( n =273) or NSS ( n =268). Outcome measurements and statistical analysis End points included follow-up estimated glomerular filtration rate (eGFR) 2 , eGFR 2 , eGFR 2 , and all-cause mortality. Treatment effect was examined within baseline variables: age ( 1.25×upper limit of normal (ULN). Logistic and Cox regression models were used for analysis of renal dysfunction and all-cause mortality, respectively. Results and limitations The median follow-up periods were 6.7 yr for eGFR and 9.3 yr for survival. No variable-by-treatment interactions were significant at alpha=0.05. For patients with baseline creatinine >1.25×ULN ( n =36), estimated mortality hazard ratio (HR) for NSS versus RN reversed its direction (HR=0.76, 95% confidence interval [CI]: 0.17–3.39) relative to the rest of the study cohort (HR=1.56, 95% CI: 1.06–2.29), although this reversal was not statistically significant (interaction p =0.25). This analysis was limited by low power. Conclusions This exploratory analysis did not reveal strong evidence of treatment effect modification in EORTC 30904, but it was limited by low power. Patient summary We aimed to determine whether the effect of partial versus radical nephrectomy on kidney function and overall survival depended on age, sex, and baseline health of patients enrolled in a large clinical trial. Such dependence could not be demonstrated in this analysis.

Summary Interval estimation is an important objective of most experimental and observational studies. Knowing at the design stage of the study how wide the confidence interval (CI) is expected to be and where its limits are expected to fall can be very informative. Asymptotic distribution of the confidence limits can also be used to answer complex questions of power analysis by computing power as probability that a CI will exclude a given parameter value. The CI-based approach to power and methods of calculating the expected size and location of asymptotic CIs as a measure of expected precision of estimation are reviewed in the present paper. The theory is illustrated with commonly used estimators, including unadjusted risk differences, odds ratios and rate ratios, as well as more complex estimators based on multivariable linear, logistic and Cox regression models. It is noted that in applications with the non-linear models, some care must be exercised when selecting the appropriate variance expression. In particular, the well-known ‘short-cut’ variance formula for the Cox model can be very inaccurate under unequal allocation of subjects to comparison groups. A more accurate expression is derived analytically and validated in simulations. Applications with ‘exact’ CIs are also considered.

Person-time incidence rates are frequently used in medical research. However, standard estimation theory for this measure of event occurrence is based on the assumption of independent and identically distributed (iid) exponential event times, which implies that the hazard function remains constant over time. Under this assumption and assuming independent censoring, observed person-time incidence rate is the maximum-likelihood estimator of the constant hazard, and asymptotic variance of the log rate can be estimated consistently by the inverse of the number of events. However, in many practical applications, the assumption of constant hazard is not very plausible. In the present paper, an average rate parameter is defined as the ratio of expected event count to the expected total time at risk. This rate parameter is equal to the hazard function under constant hazard. For inference about the average rate parameter, an asymptotically robust variance estimator of the log rate is proposed. Given some very general conditions, the robust variance estimator is consistent under arbitrary iid event times, and is also consistent or asymptotically conservative when event times are independent but nonidentically distributed. In contrast, the standard maximum-likelihood estimator may become anticonservative under nonconstant hazard, producing confidence intervals with less-than-nominal asymptotic coverage. These results are derived analytically and illustrated with simulations. The two estimators are also compared in five datasets from oncology studies.

Objective To estimate the effect of radiation therapy (RT) administered for uterine cancer (UtC) on bladder cancer (BC) incidence, tumour characteristics at presentation, and mortality. Patients and Methods In this retrospective cohort study, records of 56 681 patients diagnosed with UtC as their first primary malignancy during 1980–2005 were obtained from the Surveillance, Epidemiology and End-Results (SEER) database. Follow-up for incident BC ended on 31 December 2008. Occurrences of BC diagnoses and BC deaths in patients with UtC managed with or without RT were summarised with counts and person-time incidence rates (counts divided by person-years of observation). Age adjustment of rates was performed by direct standardisation. Incident BC cases were described in terms of histological types, grades and stages. Results With a mean follow-up of 15 years, BC was diagnosed in 146 (0.93%) of 15 726 patients with UtC managed with RT, and in 197 (0.48%) of 40 955 patients with UtC managed without RT, with an age-adjusted rate ratio of 2.0 (95% confidence interval [CI] 1.6–2.5). Fatal BC occurred in 39 (0.25%) and 36 (0.09%) of patients with UtC managed with vs without RT, respectively, with an age-adjusted rate ratio of 2.9 (95% CI 1.8–4.6). Incident BC cases diagnosed in patients with UtC managed with vs without RT had similar distributions of histological types, grades, and stages. Conclusions Use of RT for UtC is associated with increased BC incidence and mortality later in life. Heightened awareness should help identify women with new voiding symptoms or haematuria, all of which should be fully evaluated.

Introduction In EORTC trial 30904 of partial versus radical nephrectomy overall survival was significantly better in the radical nephrectomy arm. However, many observational studies reported better survival after partial than radical nephrectomy. We present an updated systematic review of observational studies of overall survival after partial versus radical nephrectomy with assessment of quality of evidence. Methods The literature search was performed until December 31, 2013, and all studies reporting overall survival after partial vs radical nephrectomy were included in the initial review. Further inclusion criteria for complete review were malignant tumors 7 cm or smaller, or benign tumors of any size, and survival analysis performed with adjustment for confounding variables. Studies not meeting these criteria were excluded from full review because of selection bias in favor of patients treated with partial nephrectomy who were younger and with less advanced tumors. Results A total of 34 studies were included in the initial review and 13 were included in the full review. The 13 studies were based on the SEER database (6) or on institutional cohorts (7). In 8 of the 13 studies the estimated hazard ratios were significantly below 1, indicating better overall survival after partial nephrectomy, while in the remaining 5 studies estimated HR was not significantly different from 1. Median HR was 0.80 (interquartile range 0.57 to 0.96, absolute range 0.40 to 1.10). Conclusions In most observational studies overall survival was better after partial than after radical nephrectomy. However, because residual confounding could be present despite adjustment for measured covariates, another randomized trial of partial vs radical nephrectomy may be needed to confirm or refute the findings of EORTC 30904.

Objectives Because bladder cancer (BC) patients often have comorbidities that adversely affect their health, we wanted to determine whether grade and stage of BC at diagnosis are associated with the hazard of death from causes other than BC. Materials and methods Cancer records for 93,033 patients diagnosed with urothelial BC during 1988–2002 were obtained from the Surveillance Epidemiology and End Results (SEER) database. The grade-stage categories were defined as follows: (1) low grade, stage 0/I (Ta/T1, N0/Nx), (2) high grade, stage 0/I (Ta/Tis/T1, N0/Nx), (3) any grade, stage II (T2, N0/Nx), (4) any grade, stage III (T3-T4a, N0/Nx), (5) any grade, stage IV (T4b and/or N+). Patients with known distant metastases at presentation were excluded. Other covariates were age, gender, and race. The outcome measures were defined as the hazard of death from all causes, from BC, and from non-BC causes. Cox regression model was used to estimate the effect of grade-stage categories on over-all and cause-specific hazards with adjustment for covariates. Results The 5-year mortality proportions by grade-stage category were as follows: low grade, stage 0/I: all-causes 25%, BC 3%, non-BC 22%; high grade stage 0/I: all-causes 38%, BC 13%, non-BC 25%; stage II: all-causes 63%, BC 36%, non-BC 27%; stage III: all-causes 69%, BC 45%, non-BC 24%; stage IV: all-causes 83%, BC 68%, non-BC 15%. Using low grade, stage 0/I as a reference category, the hazard ratios for increasing grade-stage categories (high grade 0/I, II, III, IV) were as follows: all-cause mortality 1.30, 2.37, 3.07, 6.14; BC-related hazard 3.31, 10.02, 14.65, 32.04; non-BC-related hazard: 1.05, 1.37, 1.49, 1.65 (all P Conclusion Grade-stage categories were associated with the hazard of death from non-BC causes. However, their influence on BC-related hazard was much greater in magnitude. Because BC (rather than co-morbidities) is the main cause of death in patients with muscle-invasive disease, aggressive BC-directed therapies in these patients, when feasible, are justified.

In randomized trials with imperfect compliance, it is sometimes recommended to supplement the intention-to-treat estimate with an instrumental variable (IV) estimate, which is consistent for the effect of treatment administration in those subjects who would get treated if randomized to treatment and would not get treated if randomized to control. The IV estimation however has been criticized for its reliance on simultaneous existence of complementary "fatalistic" compliance states. The objective of the present paper is to identify some sufficient conditions for consistent estimation of treatment effects in randomized trials with stochastic compliance. It is shown that in the stochastic framework, the classical IV estimator is generally inconsistent for the population-averaged treatment effect. However, even under stochastic compliance, with certain common experimental designs the IV estimator and a simple alternative estimator can be used for consistent estimation of the effect of treatment administration in well-defined and identifiable subsets of the study population.

What's known on the subject? and What does the study add? Over the last few years, several observational studies examined the association of statin use with the risk of biochemical recurrence of prostate cancer after definitive local therapy. The objective of our present study was to summarise available evidence on this subject using the method of meta-analysis. Combined evidence from eight cohort studies did not definitively support the hypothesis that statins influence the risk of biochemical recurrence. However, there was considerable disagreement between individual studies in reported findings and conclusions. OBJECTIVE • To perform a systematic review and meta-analysis of clinical studies with statin use as the exposure variable and biochemical recurrence after definitive local therapy for prostate cancer as the outcome. METHODS • Relevant publications were identified through PubMed/Medline/Embase databases. • Pooled estimates of the hazard ratios (HRs) were computed using the inverse-variance weighting approach. • Heterogeneity was assessed using the Cochran's Q test. RESULTS • We identified a total of eight eligible studies, all based on the retrospective cohort design. Five of these were based on radical prostatectomy (RP) series and three on radiotherapy (RT) series. • There was evidence of heterogeneity in the entire set of eight studies (P= 0.002) as well as in the RP series (P= 0.05) and in the RT series (P= 0.01), when these were considered separately. • Based on the random effects inverse-variance weighting approach, pooled estimates of the HRs for the risk of biochemical recurrence in statin users v non-users were 0.91 (95% confidence interval [CI] 0.72–1.13) for the entire set of eight studies, 1.02 (95% CI 0.80–1.29) for the RP series and 0.71 (95% CI 0.44–1.16) for the RT series. CONCLUSION • The pooled estimates of the HRs were not significantly different from the null value in this meta-analysis; however, evidence of heterogeneity between the studies was present.

Summary In the classical theory of randomized trials (RTs), the treatment effect is defined as a mean difference of potential outcomes. To achieve nominal coverage probability for confidence intervals (CIs) on treatment effects in RTs, certain assumptions are necessary. Specifically, one must either make assumptions about the joint distribution of potential outcomes or enroll subjects in the trial by random sampling of the target population on which the treatment effect is defined. In practice, no such sampling usually takes place and assumptions about the joint distribution of potential outcomes cannot be verified based on observed data. Furthermore, the most common of these assumptions, such as treatment-unit additivity (TUA) or independence are biologically implausible in most RTs involving human subjects. Hence, it is not usually possible to construct CIs on treatment effects with nominal coverage probability. However, for any joint distribution of potential outcomes, the standard estimator of the variance of the difference of two independent sample means produces CIs with asymptotic coverage at least at the nominal level. This interpretation of CIs as conservative bounds may not always hold in conventional regression models applied to RT data. Resume Dans la theorie classique des experiences randomisees (Randomized Trials ou RTs), l'effet-traitement est defini comme une difference entre reponses potentielles. Pour que les intervalles de confiance sur ces effets-traitements atteignent la probabilite de couverture nominale, des hypotheses sont necessaires. Soit ces hypotheses portent sur la loi jointe des reponses potentielles, soit elles concernent la facon dont sont selectionnes, par echantillonnage de populations-cibles, les sujets participant a l'experience. En pratique, de tels echantillonnages sont fictifs, et les hypotheses sur les lois jointes de reponses potentielles ne peuvent etre testees sur base d'observations. En outre, les plus repandues de ces hypotheses, telle l'hypothese d'additivite traitement-sujet (treatment-unit additivity ou TUA), sont biologiquement peu plausibles dans les experiences faisant intervenir des sujets humains. Il est donc en general impossible de construire pour les effets-traitements des intervalles de confiance dont le taux de couverture egale le niveau de confiance nominal. L'estimateur standard de la variance de la difference de deux moyennes empiriques independantes fournit des intervalles de confiance dont le niveau de couverture est au moins egal au niveau nominal. Cette interpretation conservative des intervalles de confiance n'est toutefois pas toujours correcte pour les modeles de regression conventionnels dans le cadre d'observations provenant d'experiences randomisees.

Study Type – Diagnosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Previous studies from the USA reported that, in recent years, prostate cancer screening with PSA was very common among the elderly men, including those whose life expectancy was substantially limited by advanced age and known comorbidities. In 2008, the US Preventive Services Task Force (USPSTF) recommended against PSA screening after age 75. The purpose of this study was to examine the impact of the USPSTF 2008 recommendation on the frequency of PSA testing among elderly men in the USA. Our findings suggest that the USPSTF recommendation had no major impact on clinical practice. OBJECTIVE • To examine the frequency of PSA testing in men aged ≥75 years before and after the 2008 US Preventive Services Task Force (USPSTF) recommendation to stop prostate-specific antigen (PSA) screening at age 75. MATERIALS AND METHODS • Data were obtained from the Behavioral Risk Factor Surveillance System (BRFSS) surveys completed in 2006, 2008 and 2010. • Men aged ≥ 76 years at the time of survey and without a prostate cancer diagnosis were included in the study. • The percentage of men who had a PSA test in the year before the survey was computed separately for survey years 2006, 2008 and 2010. RESULTS • The estimated percentages of men with a PSA test in the year before the survey were 60% (95% CI: 58–62%), based on 9033 respondents interviewed in 2006, 63% (95% CI: 62–65%), based on 12 063 respondents interviewed in 2008, and 60% (95% CI: 59–61%), based on 14 782 respondents interviewed in 2010. CONCLUSION • No substantial reduction in the frequency of PSA testing was observed in the BRFSS 2010 survey data compared with the earlier years, suggesting that the USPSTF 2008 recommendation had no major impact on the frequency of PSA testing in older men in the USA.

The Surveillance, Epidemiology, and End Results (SEER) program is a commonly used data source in cancer research. This article provides an introduction to the SEER database, describes important data items available from SEER on the most commonly diagnosed urologic malignancies (prostate, bladder, and kidney cancers), and reviews limitations of SEER data for urologic oncology research.

Study Type – Harms (individual cohort) Level of Evidence 2a What’s known on the subject? and What does the study add? Previously, it was appreciated that men lost about 12 years of expected remaining life if they died of bladder cancer. However, nothing was known about how exposure history, gender, age and stage at diagnosis, and other factors affected life expectancy of bladder cancer patients. The impact of these factors was now taken into consideration when determining years of potential life lost from bladder cancer death and the loss in median life expectancy at bladder cancer diagnosis. Compared with men, women lose more years of life and a greater fraction of their life expectancy to bladder cancer. OBJECTIVE • To estimate the average loss in life expectancy (LE) due to bladder cancer (BC) in men and women in the USA. PATIENTS AND METHODS • Cancer records for 51 528 patients diagnosed with BC during 1988–1997 were obtained from the Surveillance, Epidemiology, and End Results database. • Potential follow-up ranged from 10 to 20 years (median 14 years). Loss in median LE at BC diagnosis was computed as the difference between expected median survival and observed median survival. • Expected survival was calculated using two methods: method 1 used age, sex, and race-specific LE in the general population, method 2 used the hazard of death from non-BC causes in patients with BC (to account for past exposures and treatment-related toxicities not present in the general population). RESULTS • During the study period, BC death occurred in 17% of men and 23% of women and non-BC death occurred in 53% of men and 47% of women. • Using LE in the general population as the reference (method 1), loss in median LE at BC diagnosis was 3.9 years for men (33% of their potential remaining years of life) and 6.5 years for women (47% of their potential remaining years of life). • Using non-BC-specific hazard as the reference (method 2), loss in median LE was 2.7 years for men (26% of their potential remaining years of life) and 4.1 years for women (36% of their potential remaining years of life). CONCLUSION • Compared with men, women loose more years of life and a greater fraction of their life expectancy to BC.

BACKGROUND: The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down-staging of patients with locally advanced urothelial cancer (UC) of the bladder. METHODS: This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2-T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down-staging end points in the bladder (

Objectives To determine whether the survival of patients with squamous cell carcinoma (SCC) is different from that of patients with urothelial carcinoma, after adjusting for stage, grade, demographic factors, and the initial treatment. Methods Information on bladder cancer cases diagnosed from 1988 to 2003 was obtained from the Surveillance, Epidemiology, and End Results database. The tumors were classified by histologic type, grade, and American Joint Committee on Cancer (AJCC) stage. Other covariates included age, sex, race, and information on the initial treatment (cystectomy and radiotherapy). The outcome variables examined were all-cause and bladder cancer-specific mortality within 2 years of diagnosis. Covariate-adjusted mortality differences were computed within each stage using the modified least squares model. Results SCC histologic features were an independent predictor of all-cause and bladder cancer-specific mortality among patients with AJCC Stage I and II tumors who did not undergo cystectomy as a part of their initial treatment and among patients with AJCC Stage III and IV regardless of whether cystectomy was performed. SCC histologic features were not associated with increased mortality among patients with AJCC Stage I and II tumors treated with cystectomy. Conclusions SCC appears to be more aggressive than urothelial carcinoma after adjusting for stage and other prognostic factors, except for cases in which the tumor was confined to the bladder wall and the bladder was removed as a part of the initial treatment.

BACKGROUD: Sex, race, and age at diagnosis have a significant impact on mortality from bladder cancer (BC). Women, African Americans of both sexes, and the elderly, all experience higher mortality rates. Tumor grade, stage, and histologic type at presentation also affect outcome. To determine whether age and tumor characteristics alone explain the excess hazard of death from BC observed in some demographic groups, the authors queried the Surveillance, Epidemiology, and End Results (SEER) limited-use database for the presentations of and outcomes from BC between 1990 and 2005. METHODS: Tumors were characterized by grade, stage, and histologic type. Hazards rates for BC-specific mortality were compared by race and sex using a piecewise Cox regression model, adjusting for factors (age, stage, grade, and histologic type) that differed significantly between the groups that were compared. RESULTS: Excess hazard of death from BC was present during the first 2 to 3 years of follow-up among women and during the first 4 years of follow-up among African Americans. Adjustment for age and tumor characteristics eliminated approximately 30% of this excess hazard in sex comparison among whites. In sex comparison among blacks and in racial comparisons within each sex, approximately 50% to 70% of excess hazard could be eliminated by adjustment. CONCLUSIONS: Significant differences in tumor characteristics and age at presentation did not fully account for the excess hazard of death from BC among women and African Americans. Other factors, such as choice and efficacy of therapies, differences within a given tumor characteristic group, and/or host factors, also may play important roles. Cancer 2009. © 2008 American Cancer Society.

To estimate the effect of radiation therapy (RT) administered for uterine cancer (UtC) on bladder cancer (BC) incidence, tumour characteristics at presentation, and mortality.In this retrospective cohort study, records of 56 681 patients diagnosed with UtC as their first primary malignancy during 1980-2005 were obtained from the Surveillance, Epidemiology and End-Results (SEER) database. Follow-up for incident BC ended on 31 December 2008. Occurrences of BC diagnoses and BC deaths in patients with UtC managed with or without RT were summarised with counts and person-time incidence rates (counts divided by person-years of observation). Age adjustment of rates was performed by direct standardisation. Incident BC cases were described in terms of histological types, grades and stages.With a mean follow-up of 15 years, BC was diagnosed in 146 (0.93%) of 15 726 patients with UtC managed with RT, and in 197 (0.48%) of 40 955 patients with UtC managed without RT, with an age-adjusted rate ratio of 2.0 (95% confidence interval [CI] 1.6-2.5). Fatal BC occurred in 39 (0.25%) and 36 (0.09%) of patients with UtC managed with vs without RT, respectively, with an age-adjusted rate ratio of 2.9 (95% CI 1.8-4.6). Incident BC cases diagnosed in patients with UtC managed with vs without RT had similar distributions of histological types, grades, and stages.Use of RT for UtC is associated with increased BC incidence and mortality later in life. Heightened awareness should help identify women with new voiding symptoms or haematuria, all of which should be fully evaluated.

The incidence of bladder cancer varies substantially between different geographic regions, which can in part be attributed to regional differences in exposures, although differences in reporting may also play a role. In general, the incidence tends to be higher in developed countries than less developed ones. In all geographic regions, men are much more likely to be diagnosed with bladder cancer than women, and within each sex the risk of bladder cancer diagnosis increases considerably with age. Smoking remains the most important known modifiable risk factors for bladder cancer development, although other occupational and environmental exposures exist.

Person-time incidence rates are frequently used in medical research. However, standard estimation theory for this measure of event occurrence is based on the assumption of independent and identically distributed (iid) exponential event times, which implies that the hazard function remains constant over time. Under this assumption and assuming independent censoring, observed person-time incidence rate is the maximum-likelihood estimator of the constant hazard, and asymptotic variance of the log rate can be estimated consistently by the inverse of the number of events. However, in many practical applications, the assumption of constant hazard is not very plausible. In the present paper, an average rate parameter is defined as the ratio of expected event count to the expected total time at risk. This rate parameter is equal to the hazard function under constant hazard. For inference about the average rate parameter, an asymptotically robust variance estimator of the log rate is proposed. Given some very general conditions, the robust variance estimator is consistent under arbitrary iid event times, and is also consistent or asymptotically conservative when event times are independent but nonidentically distributed. In contrast, the standard maximum-likelihood estimator may become anticonservative under nonconstant hazard, producing confidence intervals with less-than-nominal asymptotic coverage. These results are derived analytically and illustrated with simulations. The two estimators are also compared in five datasets from oncology studies.

In Neyman’s causal model (NCM), each subject participating in a two-arm randomized trial has a pair of potential outcomes – one outcome would be observed under treatment and another under control. In the stochastic version of NCM the two potential outcomes are viewed as possibly non-degenerate random variables with finite expectations and variances. The subject-level treatment effect is the expected outcome under treatment minus that under control, and the average treatment effect is the arithmetic mean of the subject-level effects. In the present paper properties of the ordinary “difference of means” estimator and its associated variance estimator are examined in the completely randomized design with stochastic potential outcomes. Estimation theory is developed under randomization distribution without commitment to any particular probability model for enrollment, because in real trials subjects are not enrolled by a sampling mechanism with known selection probabilities. It is shown that in this theoretical framework, the “difference of means” estimator is asymptotically normal and consistent for the average treatment effect in the study cohort, while its associated variance estimator is conservative, producing confidence intervals with at least nominal asymptotic coverage. The proofs are not trivial because in the randomization framework sample means under treatment and control are correlated random variables.

In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with reduced overall survival compared with radical nephrectomy (RN) over a median follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval [CI], 1.03-2.16).To examine the impact of NSS relative to RN on kidney function in EORTC 30904.This phase 3 international randomized trial was conducted in patients with a small (≤5 cm) renal mass and normal contralateral kidney who were enrolled from March 1992 to January 2003.Patients were randomized to RN (n=273) or NSS (n=268).Follow-up estimated glomerular filtration rates (eGFR; milliliters per minute per 1.73 m(2)) were recorded for 259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of subjects developing at least moderate renal dysfunction (eGFR60), advanced kidney disease (eGFR30), or kidney failure (eGFR15) were calculated for each treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat analysis).With a median follow-up of 6.7 yr, eGFR60 was reached by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI, 13.8-28.3); eGFR30 was reached by 10.0% with RN and 6.3% with NSS, with a difference of 3.7% (95% CI, -1.0 to 8.5); and eGFR15 was reached by 1.5% with RN and 1.6% with NSS, with a difference of -0.1% (95% CI, -2.2 to 2.1). Lack of longer follow-up for eGFR is a limitation of these analyses.Compared with RN, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR60), although with available follow-up the incidence of advanced kidney disease (eGFR30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR15) was nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population.EORTC trial 30904; ClinicalTrials.gov identifier NCT00002473.

Background The objective of this study was to estimate the total number of patients who would be expected to present with metastatic (M1) prostate cancer (PC) in the modern US population in a given year if the age-specific and race-specific annual incidence rates of M1 PC were the same as the rates in the era before prostate-specific antigen (PSA) testing. Methods The authors computed the total number of men who presented with M1 PC in the Surveillance, Epidemiology, and End Results (SEER) 9 registries area in the year 2008 (the most recent SEER year) and estimated the number of cases that would be expected to occur in this area in the year 2008 in the absence of PSA testing. The expected number was computed by multiplying each age-race-specific average annual incidence rate from the pre-PSA era (1983-1985) by the number of men in the corresponding age-race category in the year 2008 and adding the products. Results In the year 2008, the observed and expected numbers of men presenting with M1 PC in the SEER 9 registries area were 739 and 2277, respectively, with an expected-to-observed ratio of 3.1 (95% confidence interval, 3.0-3.2). If this ratio was applied to the total US population in the year 2008, then the total number of men presenting with M1 PC in that year would be equal to approximately 25,000 instead of the approximately 8000 actually observed. Conclusions If the pre-PSA era rates were present in the modern US population, then the total number of men presenting with M1 PC would be approximately 3 times greater than the number actually observed.

What's known on the subject? and What does the study add? Over the last few years, several observational studies examined the association of statin use with the risk of biochemical recurrence of prostate cancer after definitive local therapy. The objective of our present study was to summarise available evidence on this subject using the method of meta-analysis. Combined evidence from eight cohort studies did not definitively support the hypothesis that statins influence the risk of biochemical recurrence. However, there was considerable disagreement between individual studies in reported findings and conclusions.To perform a systematic review and meta-analysis of clinical studies with statin use as the exposure variable and biochemical recurrence after definitive local therapy for prostate cancer as the outcome.Relevant publications were identified through PubMed/Medline/Embase databases. Pooled estimates of the hazard ratios (HRs) were computed using the inverse-variance weighting approach. Heterogeneity was assessed using the Cochran's Q test.We identified a total of eight eligible studies, all based on the retrospective cohort design. Five of these were based on radical prostatectomy (RP) series and three on radiotherapy (RT) series. There was evidence of heterogeneity in the entire set of eight studies (P = 0.002) as well as in the RP series (P = 0.05) and in the RT series (P = 0.01), when these were considered separately. Based on the random effects inverse-variance weighting approach, pooled estimates of the HRs for the risk of biochemical recurrence in statin users v non-users were 0.91 (95% confidence interval [CI] 0.72-1.13) for the entire set of eight studies, 1.02 (95% CI 0.80-1.29) for the RP series and 0.71 (95% CI 0.44-1.16) for the RT series.The pooled estimates of the HRs were not significantly different from the null value in this meta-analysis; however, evidence of heterogeneity between the studies was present.

INTRODUCTION AND OBJECTIVES: The objective of this study was to examine the frequency of PSA testing in men 75 years old and older in years before and after the 2008 US Preventive Services Task Force (USPSTF) recommendation to stop PSA screening at age 75. METHODS: Data were obtained from the Behavioral Risk Factor Surveillance System (BRFSS) surveys completed in years 2006, 2008, and 2010. Men age 76 and older at the time of survey and without a PC diagnosis were included in the study. The percentage of men who had a PSA test in the past year before the survey was computed separately for survey years 2006, 2008, and 2010. RESULTS: The estimated percentages of men with a PSA test in the past year before the survey were 60% (95%CI: 58%-62%) based on 9,033 respondents interviewed in year 2006, 63% (95%CI: 62%65%) based on 12,063 respondents interviewed in year 2008, and 60% (95%CI: 59%-61%) based on 14,782 respondents interviewed in year 2010. CONCLUSIONS: No substantial reduction in the frequency of PSA testing was observed in the BRFSS 2010 survey data compared to the earlier years, suggesting that the USPSTF 2008 recommendation had no major impact on the frequency of PSA testing in older men in the US.

increased log odds of functional erections after treatment (all p

To examine the frequency of PSA testing in men aged ≥75 years before and after the 2008 US Preventive Services Task Force (USPSTF) recommendation to stop prostate-specific antigen (PSA) screening at age 75.Data were obtained from the Behavioral Risk Factor Surveillance System (BRFSS) surveys completed in 2006, 2008 and 2010. Men aged ≥ 76 years at the time of survey and without a prostate cancer diagnosis were included in the study. The percentage of men who had a PSA test in the year before the survey was computed separately for survey years 2006, 2008 and 2010.The estimated percentages of men with a PSA test in the year before the survey were 60% (95% CI: 58-62%), based on 9033 respondents interviewed in 2006, 63% (95% CI: 62-65%), based on 12,063 respondents interviewed in 2008, and 60% (95% CI: 59-61%), based on 14,782 respondents interviewed in 2010.No substantial reduction in the frequency of PSA testing was observed in the BRFSS 2010 survey data compared with the earlier years, suggesting that the USPSTF 2008 recommendation had no major impact on the frequency of PSA testing in older men in the USA.

BACKGROUND: The objective of this study was to estimate the total number of patients who would be expected to present with metastatic (M1) prostate cancer (PC) in the modern US population in a given year if the age-specific and race-specific annual incidence rates of M1 PC were the same as the rates in the era before prostate-specific antigen (PSA) testing. METHODS: The authors computed the total number of men who presented with M1 PC in the Surveillance, Epidemiology, and End Results (SEER) 9 registries area in the year 2008 (the most recent SEER year) and estimated the number of cases that would be expected to occur in this area in the year 2008 in the absence of PSA testing. The expected number was computed by multiplying each age-race–specific average annual incidence rate from the pre-PSA era (1983-1985) by the number of men in the corresponding age-race category in the year 2008 and adding the products. RESULTS: In the year 2008, the observed and expected numbers of men presenting with M1 PC in the SEER 9 registries area were 739 and 2277, respectively, with an expected-to-observed ratio of 3.1 (95% confidence interval, 3.0-3.2). If this ratio was applied to the total US population in the year 2008, then the total number of men presenting with M1 PC in that year would be equal to approximately 25,000 instead of the approximately 8000 actually observed. CONCLUSIONS: If the pre-PSA era rates were present in the modern US population, then the total number of men presenting with M1 PC would be approximately 3 times greater than the number actually observed. Cancer 2012. © 2012 American Cancer Society.

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? In a meta-analysis of randomized trials, neoadjuvant platinum-based combination chemotherapy administered before definitive local treatment improved survival of patients with muscle-invasive bladder cancer compared with definitive local treatment alone. However, it was not known whether chemotherapy was equally effective for pure urothelial carcinoma versus urothelial carcinoma with mixed histological features, such as squamous or glandular differentiation. To address this question we performed a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone for treatment of locally advanced urothelial cancer of the bladder. Our findings suggest that presence of squamous or glandular differentiation does not confer resistance to combination chemotherapy with MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy. OBJECTIVE • To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of non-urothelial components in the tumour. PATIENTS AND METHODS • This is a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder. • For the purpose of these analyses, tumours were classified based on the presence of non-urothelial components as either pure UC (n= 236) or mixed tumours (n= 59). Non-urothelial components included squamous and glandular differentiation. • Cox regression models were used to estimate the effect of neoadjuvant MVAC on all-cause mortality for patients with pure UC and for patients with mixed tumours, with adjustment for age and clinical stage. RESULTS • There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25–0.87; P= 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67–1.21; P= 0.48). • There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P= 0.09). CONCLUSION • Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.

The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down-staging of patients with locally advanced urothelial cancer (UC) of the bladder.This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2-T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down-staging end points in the bladder (pT1,pT2,pT3), nodal status, and surgical margins. Linear probability models were used to estimate the effect of neoadjuvant GC on tumor down-staging with adjustment for clinical staging variables.A total of 160 eligible patients were identified, of whom 25 were treated with neoadjuvant GC before RC (GC + RC) and 135 without neoadjuvant chemotherapy (RC only). Stage pT0 at cystectomy was found in 20% of patients in the GC + RC group and in 5% of patients in the RC group (adjusted risk difference [aRD] = 16%, P = .03). For other down-staging end points, the estimated treatment effect was as follows (all point estimates favoring chemotherapy):pT1 aRD = 30% (P = .005);pT2 aRD = 30% (P = .004);pT3 aRD = 31% (P = .008); margins aRD = 8% (P = .41); nodes aRD = 4% (P = .74).Neoadjuvant GC was found to be capable of down-staging UC in the bladder; however, no effect on disease in nodes was seen in this study.

Purpose of review Women are generally less likely to develop bladder cancer compared with men; however, once they acquire this disease, they have a less favorable prognosis. In this review, we describe our current understanding of the relationship between sex and bladder cancer incidence and outcomes and discuss the most recent developments in this area of research. Recent findings Despite some evidence suggesting involvement of hormonal factors in bladder cancer carcinogenesis, the exact mechanisms responsible for increased bladder cancer incidence in men are still incompletely understood. The causes of increased mortality in women are also unclear. It has been hypothesized that women present with more advanced stages (and thus have inferior survival) than men because early signs of bladder cancer in women are often attributed to more common benign conditions. However, recent studies have shown that excess mortality in women persists after adjustment for stage and other tumor characteristics. Women also do not appear to be significantly undertreated for bladder cancer. Summary Despite considerable research efforts, both increased incidence in men and decreased survival in women remain somewhat of a mystery. The causes of these phenomena may include poorly understood biological factors or environmental influences, which may become a subject of future research.

OBJECTIVE To determine whether microscopic invasion of perivesical fat by urothelial carcinoma (stage pT3a) confers a different prognosis relative to deep muscle invasion (pT2b) and/or gross extravesical extension (pT3b) among patients with a given nodal status treated by cystectomy. METHODS Cancer records for patients diagnosed with stage pT2b-pT3b bladder cancer from 1998-2006 were obtained from the SEER database (n = 2388). Pathologic substage (pT3a vs pT2b vs pT3b) was the primary covariate of interest. Other covariates included age, sex, race, grade, number of nodes examined, number of positive nodes, nodal stages, and radiotherapy. Cox regression model was used to estimate the covariate-adjusted effect of tumor substages on all-cause mortality. RESULTS The risk of nodal metastases increased with increasing substage (pT2b = 20%, pT3a = 36%, pT3b = 48%, trend P

Purpose To examine the association between extended-duration prophylaxis (EDP), low-molecular-weight heparin prophylaxis for 28 days after surgery for urologic cancer in patients at high risk of developing a venous thromboembolism (VTE), the risk of VTE, and the complications resulting from VTE prophylaxis. Materials and methods The cohort included 332 patients at high risk for VTE who were surgically treated for urologic cancer from June 2011 to June 2014. Adherence to VTE prophylaxis protocol, VTEs, and complications within 365 days from surgery were tracked. Patients were grouped as follows: (1) per protocol in-hospital prophylaxis with EDP ( n = 107), (2) per protocol in-hospital prophylaxis without EDP ( n = 42), (3) not per protocol in-hospital prophylaxis with EDP ( n = 83), and (4) not per protocol in-hospital prophylaxis without EDP ( n = 100). The risk of VTE was compared between the 4 groups using the Cox model, with adjustment for baseline risk factors. Results The rates of VTEs and median times to VTE were 7% and 58 days in group 1, 17% and 44 days in group 2, 17% and 46 days in group 3, and 21% and 15 days in group 4, respectively. Adjusted hazard ratios (HR) for VTE were HR = 0.27 (95% CI: 0.11–0.70) for groups 1 vs. 4; HR = 0.66 (95% CI: 0.25–1.60) for groups 2 vs. 4; and HR = 0.66 (95% CI: 0.29–1.26) for groups 3 vs. 4 with a trend of P = 0.002. The incidence of complications from VTE prophylaxis was not significantly different between the groups, with a rate of 8% in group 1, 17% in group 2, 6% in group 3, and 12% in group 4 ( P = 0.33). Conclusions In high-risk urologic cancer surgery patients, a clinical protocol, with perioperative and EDP, is safe and effective in reducing VTE events.

The human immunodeficiency virus (HIV) pandemic is unique in human history in its rapid spread, its persistence, and the depth of its impact. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that approximately 65 million people have been infected with HIV since the beginning of the epidemic. During this time, approximately 25 million people have died from acquired immune deficiency syndrome AIDS. HIV-associated morbidity and mortality was substantially reduced during the last decade following the introduction of highly active antiretroviral therapy (HAART). In spite of the striking success of HAART in treating HIV infection, many patients experience treatment failure as genetic changes emerge in the virus leading to drug resistance. Laboratory testing for drug resistance in HIV strains is now used in combination with other methods to guide antiretroviral therapy. The purpose of this report is to review the background information on HIV with the focus on the problem of drug resistance and to describe the laboratory methods of testing for drug resistance in HIV strains.

In Neyman’s causal model (NCM), each unit included in a two-arm randomized experiment has a pair of potential outcomes – one outcome would be observed under treatment, the other under control. In the stochastic version of NCM, both potential outcomes are viewed as (possibly) non-degenerate random variables to allow for stochastic effects of post-interventional factors, such as random measurement error. The unit-level treatment effect is the expected outcome under treatment minus that under control. The sample average treatment effect (SATE) is the mean of the unit-level effects in the set of all units included in the experiment. The population average treatment effect (PATE) is the mean of the unit-level effects defined on the population of all units eligible for experiment. The purpose of this paper is to develop a non-parametric theory of inference about SATE and PATE in block-randomized experiments, using the mathematical formalism of stochastic NCM. Inference about SATE is examined under randomization distribution without a probability model for selection of units into experiment. For inference about PATE two probability models for selection are considered: (1) simple random sampling and (2) stratified random sampling, each followed by block-randomized treatment assignment. It is shown that under these conditions, the ordinary “difference of means” estimator (mean observed outcome under treatment minus that under control) is consistent for both SATE and PATE. The variance of this estimator is derived under randomization distribution alone and under simple random sampling and stratified random sampling as selection models. Variance estimators producing confidence intervals with nominal asymptotic coverage for PATE under these selection models are proposed, and it is also shown that these intervals have at least nominal asymptotic coverage for SATE under randomization distribution. Thus, when a selection model is correctly specified, the proposed methods guarantee valid inference about both SATE and PATE, while under incorrect specification of the selection model valid inference about SATE is still guaranteed. This is an important property because in many types of randomized experiments (e.g., clinical trials in medicine), units are not selected into experiment by a mechanism with known selection probabilities.

Objectives In the United States, among patients diagnosed with bladder cancer (BC), women have increased disease-specific mortality compared with men. The main objective of this study was to determine whether this pattern is also present in other countries. For comparison, similar analyses were performed for kidney cancer (KC). Methods and materials Data for this study were obtained from the GLOBOCAN 2008 database. A total of 49 countries with available information on BC and KC incidence and mortality were included in the analysis, representing all major geographic regions except Africa. For each country, we computed the sex-specific ratio of the total number of deaths from a given cancer to the total number of diagnoses in the year 2008 (the mortality-to-incidence ratio [MIR]). The relative MIR was computed for each country as a ratio of MIR in women to MIR in men. A relative MIR of more than 1 would indicate that the number of cancer-specific deaths relative to the number of cancer-specific diagnoses is greater in women than in men. Results For BC, the relative MIRs were significantly more than 1 in 26 countries (53%), significantly less than 1 in 2 countries (4%), and not significantly different from 1 in 21 countries (43%). The median relative MIR was 1.21 (interquartile range: 1.04–1.41). For KC, the relative MIRs were significantly more than 1 in 4 countries (8%), significantly less than 1 in 3 countries (6%), and not significantly different from 1 in 42 countries (86%). The median relative MIR was 1.00 (interquartile range: 0.94–1.06). Conclusion Among BC patients, increased disease-specific mortality in women compared with men appears to be a common (although not a universal) phenomenon. This pattern may potentially be explained by differences between the sexes in the biology of disease, time to diagnosis, treatment decisions, and other factors. In contrast, among KC patients, no significant differences in disease-specific mortality were seen between the 2 sexes in the overwhelming majority of the countries.

In many practical problems of biology, medicine, and social sciences, inference about population mean has to be made froma sample generated with unknown selection probabilities that may vary between the units in the population. The most common approach to analysis of such samples is to use the ordinary sample mean as an estimator of population mean, under the assumption that the sample is “representative” of the population, although the concept of representative sampling is not given a formal mathematical definition. The main objective of this paper is to identify a necessary and sufficient condition for unbiasedness of the ordinary sample mean under unequal probability sampling. It is shown that in the process of sampling with unequal selection probabilities with a fixed sample size, expectation of the ordinary sample mean is exactly equal to population mean plus the covariance of the unit-level outcome with the unit-level relative selection probability, where the relative selection probability is defined as the ratio of the unit’s selection probability to the mean selection probability in the population. Hence, ordinary sample mean is unbiased if and only if the unit-level outcome is uncorrelated with the unit-level relative selection probability. Samples generated under this condition may be considered “representative” of the population for the purpose of inference about population mean. It is also shown that under representative sampling, asymptotically conservative confidence intervals for population mean can be constructed based on the ordinary sample variance estimator as long as there are no positive correlations among the sample observations (negative correlations are allowed) and conditions for asymptotic normality of the sample mean are satisfied.