Exaggeration of PFS by blinded, independent, central review (BICR).

BACKGROUND: Recent published studies have shown meaningful discrepancies between local investigator and blinded, independent, central review (BICR) assessed median progression-free survival (PFS). When the local review but not BICR shows progression, generally, no further assessments are carried out and patients are censored in the BICR analysis, leading to violation of the statistical assumptions of independence between censoring and outcome used in survival analysis methods. METHODS: We carried out a simulation study to assess methodological reasons behind these discrepancies and corroborated our findings in a case study of three BRCA-mutated ovarian cancer trials. We briefly outline possible methodological solutions that may lead to improved estimation of the BICR medians. RESULTS: The Kaplan-Meier (KM) curve for the BICR PFS can often be exaggerated. The degree of bias is largest when there is reasonably strong correlation between BICR and local PFS, especially when PFS is long compared with assessment frequency. This can result in an exaggeration of the medians and their difference; however, the hazard ratio (HR) is much less susceptible to bias. Our simulation shows that when the true BICR median PFS was 19 months, and patients assessed every 12 weeks, the estimated KM curves were materially biased whenever the correlation between BICR and local PFS was 0.4 or greater. This was corroborated by case studies where, in the active arm, the BICR median PFS was between 6 and 11 months greater than the local median PFS. Further research is required to find improved methods for estimating BICR survival curves. CONCLUSIONS: In general, when there is a difference between local and BICR medians, the true BICR KM curve is likely to be exaggerated and its true median will probably lie somewhere between the observed local and BICR medians. Presentation of data should always include both BICR and local results whenever a BICR is carried out.

Routine acid decalcification of bone marrow samples can preserve DNA for FISH and CGH studies in metastatic prostate cancer.

Production of paraffin-section material from tissue samples that contain bone requires decalcification. Techniques such as acidic decalcification or EDTA chelation are suitable methods. Acid decalcification is generally quicker than EDTA chelation but studies have suggested that it may result in hydrolysis of DNA. Here we show that limited acid decalcification (less than 24 hr) in 5% formic acid can preserve DNA sufficient for fluorescent in situ hybridization (FISH) or comparative genomic hybridization (CGH) and that prolonged 10% formic acid decalcification results in failure of FISH and only limited retrieval of DNA for CGH studies.

Technical basis for EPA's proposed regulation on the cleanup of sites contaminated with radioactivity.

The U.S. Environmental Protection Agency is proposing a regulation for the protection of the public from radioactive contamination at sites that are to be cleaned up and released for public use. The rule will apply to sites under the control of Federal agencies, and will impose limits on radiation doses to individuals living or working on a site following cleanup; it will thereby provide site owners and managers with uniform, consistent cleanup criteria for planning and carrying out remediation. This paper presents an overview of EPA's approach to assessing some of the beneficial and adverse effects associated with various possible values for the annual dose limit. In particular, it discusses the method developed to determine how the choice of cleanup criterion affects (1) the time-integrated potential numbers of non-fatal and fatal radiogenic cancers averted among future populations, (2) the occurrence of radiogenic cancers among remediation workers and the public caused by the cleanup process itself, and (3) the volumes of contaminated soil that may require remediation. The analytic methods described here were used to provide input data and assumptions for the Regulatory Impact Analysis (RIA) that supports the proposed regulation; the RIA also considered non-radiological benefits and costs (i.e., public health, economic, and ecological) of the standards.

Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals.

We aimed to identify cerebrospinal fluid (CSF) biomarkers associated with neurodegeneration in individuals with and without CSF evidence of Alzheimer pathology. We investigated 287 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects (age=74.9±6.9; 22/48/30% with Alzheimer's disease/mild cognitive impairment/controls) with CSF multiplex analyte data and serial volumetric MRI. We calculated brain and hippocampal atrophy rates, ventricular expansion and Mini Mental State Examination decline. We used false discovery rate corrected regression analyses to assess associations between CSF variables and atrophy rates in individuals with and without amyloid pathology, adjusting in stages for tau, baseline volume, p-tau, age, sex, ApoE4 status and diagnosis. Analytes showing statistically significant independent relationships were entered into reverse stepwise analyses. Adjusting for tau, baseline volume, p-tau, age, sex and ApoE4, 4/83 analytes were significantly independently associated with brain atrophy rate, 1/83 with ventricular expansion and 2/83 with hippocampal atrophy. The strongest CSF predictor for the three atrophy measures was low trefoil factor 3 (TFF3). High cystatin C (CysC) was associated with higher whole brain atrophy and hippocampal atrophy rates. Lower levels of vascular endothelial growth factor and chromogranin A (CrA) were associated with higher whole brain atrophy. In exploratory reverse stepwise analyses, lower TFF3 was associated with higher rates of whole brain, hippocampal atrophy and ventricular expansion. Lower levels of CrA were associated with higher whole brain atrophy rate. The relationship between low TFF3 and increased hippocampal atrophy rate remained after adjustment for diagnosis. We identified a series of CSF markers that are independently associated with rate of neurodegeneration in amyloid-positive individuals. TFF3, a substrate for NOTCH processing may be an important biomarker of neurodegeneration across the Alzheimer spectrum.

Reduced sample sizes for atrophy outcomes in Alzheimer's disease trials: baseline adjustment.

Cerebral atrophy rate is increasingly used as an outcome measure for Alzheimer's disease (AD) trials. We used the Alzheimer's disease Neuroimaging initiative (ADNI) dataset to assess if adjusting for baseline characteristics can reduce sample sizes. Controls (n = 199), patients with mild cognitive impairment (MCI) (n = 334) and AD (n = 144) had two MRI scans, 1-year apart; approximately 55% had baseline CSF tau, p-tau, and Abeta1-42. Whole brain (KN-BSI) and hippocampal (HMAPS-HBSI) atrophy rate, and ventricular expansion (VBSI) were calculated for each group; numbers required to power a placebo-controlled trial were estimated. Sample sizes per arm (80% power, 25% absolute rate reduction) for AD were (95% CI): brain atrophy = 81 (64,109), hippocampal atrophy = 88 (68,119), ventricular expansion = 118 (92,157); and for MCI: brain atrophy = 149 (122,188), hippocampal atrophy = 201 (160,262), ventricular expansion = 234 (191,295). To detect a 25% reduction relative to normal aging required increased sample sizes approximately 3-fold (AD), and approximately 5-fold (MCI). Disease severity and Abeta1-42 contributed significantly to atrophy rate variability. Adjusting for 11 predefined covariates reduced sample sizes by up to 30%. Treatment trials in AD should consider the effects of normal aging; adjusting for baseline characteristics can significantly reduce required sample sizes.

Assessing the contribution of fibrinogen in predicting risk of death in men with peripheral arterial disease.

BACKGROUND: Although fibrinogen is known to be an independent population-level risk factor for cardiovascular disease in healthy individuals, less is known about its value for individual-level risk prediction. OBJECTIVES: To assess the independent contribution of plasma fibrinogen to risk prediction in men with peripheral arterial disease. PATIENTS AND METHODS: We used data from the 785 men randomized to placebo in the Lower Extremity Arterial Disease Event Reduction (LEADER) trial. Men were followed at 6-monthly intervals up to 3 years, during which 116 patients died. Multivariable standard and pooled logistic regression were used to model odds of death in the next 3 years or in a 6-month interval. The c-statistic and predictiveness curves were used to assess improvement in predictive ability. RESULTS: Fibrinogen measured at baseline was an independent predictor of all-cause mortality risk (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.02-1.94, for a 1 g L(-1) increase). Adding baseline fibrinogen to a set of other risk factors did not, however, substantially improve predictive ability. Similarly, fibrinogen measured at the start of a 6-month interval was independently associated with odds of death in the next 6 months (adjusted OR 1.65; 95% CI 0.96-2.73). Again, predictiveness curves with and without fibrinogen did not substantially differ, although the c-statistic increased by 0.011. CONCLUSIONS: Although fibrinogen was independently associated with both 6-month and 3-year mortality risk, individual-level risk prediction was not substantially improved by including fibrinogen in risk models.

Effect of insulin on phosphorus metabolism in red blood cells from patients with schizophrenia and psychotic depressions.

In an exploratory study of the metabolism of selected intermediates of glycolysis in rbc of patients with schizophrenia and with major depressive disorders, statistically significant decreases in the RSA of 2,3-DPG were found in the rbc of patients with psychotic disorders compared to normal subjects. No statistically significant differences were observed in the RSA of any of the other glycolytic intermediates studied comparing patients to normal subjects.