Effective screening and prevention strategies for bladder cancer require accurate risk stratification models. We developed models to predict the risk of bladder cancer based on clinical and ...sociodemographic data on participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial.
Baseline clinical and sociodemographic data were obtained from 149,542 PLCO participants, ages 55 to 74 years, without a prior history of bladder cancer. Cox proportional hazards models were used to predict the risk of all bladder cancers (ABC) and of high-grade bladder cancers (HGBC) from baseline information. We used the HGBC risk model to design a hypothetical bladder cancer mortality prevention trial.
Over a median follow-up of 12 years, 1,124 men and 259 women developed bladder cancer (including 392 and 72 with HGBC, respectively). The incidence in men and in women was 133.6 and 29.6 cases per 100,000 person-years, respectively. Nomograms constructed for predicting the risk of ABC and HGBC had c-indices of 0.746 and 0.759, respectively. Age, race, education, smoking (intensity and duration), comorbidity, prostatitis, syphilis, and hormone replacement therapy use were statistically significant predictors in the models. We show that our risk model can be used to design a bladder cancer mortality prevention trial half the size of a trial designed without risk stratification.
Models to predict the risk of ABC and HGBC have been developed and validated.
Using the upper 40th percentile from the HGBC model, a suitable cohort for a screening or chemoprevention trial could be identified, although the size and follow-up of such a trial would be costly.
Older people with less education have substantially higher prevalence rates of mobility disability. This study aimed to establish the relative contributions of incidence, recovery rates, and death to ...prevalence differences in mobility disability associated with educational status.
Data were from 3 sites of the Established Populations for Epidemiological Study of the Elderly, covering 8,871 people aged 65-84 years who were followed for up to 7 years. Participants were classified on years of education received and as disabled if they needed help or were unable to walk up or down stairs or walk half a mile. A Markov model computed relative risks, adjusting for the effects of repeated observations on the same individuals.
Differences between education groups in person-years lived with disability were large. The relative risk of incident disability in men with 0-7 years of education (vs. those with 12 or more years) was 1.65 (95% CI = 1.37-1.97) and in women was 1.70 (95% CI = 1.15-2.53). Both recovery risks and risks of death in those with disability were not significantly different across education groups in either gender.
Higher incidence of disability is the main contributor to the substantially higher prevalence of disability in older people of lower socioeconomic status. Efforts to reduce the disparity in disability rates by socioeconomic status in old age should focus mainly on preventing disability, because differences in the course of mobility disability after onset appear to play a limited role in the observed prevalence disparities.
We discuss several approaches to defining power in studies designed around
the Benjamini-Hochberg (BH) false discovery rate (FDR) procedure. We focus
primarily on the \textit{average power} and the ...$\lambda$-\textit{power}, which
are the expected true positive fraction and the probability that the true
positive fraction exceeds $\lambda$, respectively. We prove results concerning
strong consistency and asymptotic normality for the positive call fraction
(PCF), the true positive fraction (TPF) and false discovery fraction (FDF).
Convergence of their corresponding expected values, including a convergence
result for the average power, follow as a corollaries. After reviewing what is
known about convergence in distribution of the errors of the plugin procedure,
(Genovese, 2004), we prove central limit theorems for fully empirical versions
of the PCF, TPF, and FDF, using a result for stopped stochastic processes. The
central limit theorem (CLT) for the TPF is used to obtain an approximate
expression for the $\lambda$-power, while the CLT for the FDF is used to
introduce an approximate procedure for determining a suitably small nominal FDR
that results in a speicified bound on the FDF with stipulated high probability.
The paper also contains the results of a large simulation study covering a
fairly substantial portion of the space of possible inputs encountered in
application of the results in the design of a biomarker study, a micro-array
experiment and a GWAS study.
Designed gene expression micro-array experiments, consisting of several
treatment levels with a number of replicates per level, are analyzed by
applying simple tests for group differences at the per ...gene level. The gene
level statistics are sorted and a criterion for selecting important genes which
takes into account multiplicity is applied. A caveat arises in that true
signals (genes truly over or under expressed) are "competing" with fairly large
type I error signals. False positives near the top of a sorted list can occur
when genes having very small fold-change are compensated by small enough
variance to yield a large test statistic. One of the first attempts around this
caveat as the development of "significance analysis of micro-arrays (SAM)",
which used a modified t-type statistic thresholded against its permutation
distribution. The key innovation of the modified t-statistic was the addition
of a constant to the per gene standard errors in order to stabilize the
coefficient of variation of the resulting test statistic. Since then, several
authors have proposed the use of shrinkage variance estimators in conjunction
with t-type, and more generally, ANOVA type tests at the gene level. Our new
approach proposes the use of a shrinkage variance Hotelling T-squared statistic
in which the per gene sample covariance matrix is replaced by a shrinkage
estimate borrowing strength from across all genes. It is demonstrated that the
new statistic retains the F-distribution under the null, with added degrees of
freedom in the denominator. Advantages of this class of tests are (i)
flexibility in that a whole family of hypothesis tests is possible (ii) the
gains of the above-mentioned earlier innovations are enjoyed more fully. This
paper summarizes our results and presents a simulation study benchmarking the
new statistic against another recently proposed statistic.
Recently, selected reaction monitoring mass spectrometry (SRM-MS) has been more frequently applied to measure low abundance biomarker candidates in tissues and biofluids, owing to its high ...sensitivity and specificity, simplicity of assay configuration, and exceptional multiplexing capability. In this study, we report for the first time the development of immunoaffinity depletion-based workflows and SRM-MS assays that enable sensitive and accurate quantification of total and free prostate-specific antigen (PSA) in serum without the requirement for specific PSA antibodies. Low ng/mL level detection of both total and free PSA was consistently achieved in both PSA-spiked female serum samples and actual patient serum samples. Moreover, comparison of the results obtained when SRM PSA assays and conventional immunoassays were applied to the same samples showed good correlation in several independent clinical serum sample sets. These results demonstrate that the workflows and SRM assays developed here provide an attractive alternative for reliably measuring candidate biomarkers in human blood, without the need to develop affinity reagents. Furthermore, the simultaneous measurement of multiple biomarkers, including the free and bound forms of PSA, can be performed in a single multiplexed analysis using high-resolution liquid chromatographic separation coupled with SRM-MS. This article is part of a Special Issue entitled: Translational Proteomics.
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► Measurement of serum total and free PSA without specific PSA antibodies. ► Low ng/mL LOQ for both total and free PSA measurement. ► Good correlation with immunoassay tests (R2 0.90–0.99). ► Biomarkers with similar complexation properties can be measured simultaneously.
OBJECTIVES: This study examined sex differences in the prevalence of mobility disability in older adults according to the influences of three components of prevalence: disability incidence, recovery ...from disability, and mortality. METHODS: Participants in a population-based study of older adults from three communities in the United States (N = 10,263) were studied for up to 7 years. Life table methods were used to estimate the influence of each of the three components of disability prevalence in women and men. Sex differences in probabilities for transition states were measured by relative risks derived from a single model using a Markov chain approach. RESULTS: The proportion of disabled women increased from 22% of women aged 70 years to 81% of those aged 90 years. In men, comparable figures were 15% and 57%. Incidence had the greatest impact on the sex differences in disability prevalence until age 90 and older when recovery rates had a greater impact on differences in prevalence. Mortality differences in men and women had only a modest impact on sex differences in disability prevalence. These findings initially seemed to contradict striking sex differences observed in the relative risks for mortality in men compared with women. Subsequent graphical analyses showed that incidence rather than recovery or mortality largely accounted for sex differences in disability prevalence in old age. CONCLUSION: Disability incidence, recovery from disability, and mortality dynamically influence the sex differences in the prevalence of mobility disability. However, incidence has the greatest impact overall on the higher prevalence of disability in women compared with men.
Objective: This paper presents a methodology for piecing together disparate data sources to obtain a comprehensive model for the use of mammography screening in the US population for the years ...1975-2000. Methods: Two aspects of mammography usage, the age that a woman receives her first mammography and the interval between subsequent mammograms, are modeled separately. The initial dissemination of mammography is based on cross-sectional self report data from national surveys and the interval length between screening exams is fit using longitudinal mammography registry data. Results: The two aspects of mammography usage are combined to simulate screening histories for individual women that are representative of the US population. Simulated mammography patterns for the years 1994-2000 were found to be similar to observed screening patterns from the state level mammography registry for Vermont. Conclusions: The model presented gives insight into screening practices over time and provides an alternative public health measure for screening usage in the US population. The comprehensive description of mammography use from its introduction represents an important first step to understanding the impact of mammography on breast cancer incidence and mortality.
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