143,744 research outputs found
Proteome-based plasma biomarkers for Alzheimer's disease
Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and α-2-macroglobulin (α- 2M). Using semi-quantitative immunoblotting, the elevation of CFH and α- 2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as α- 2M may be a specific markers of this illness. © 2006 The Author(s).link_to_subscribed_fulltex
A Weighted Prognostic Covariate Adjustment Method for Efficient and Powerful Treatment Effect Inferences in Randomized Controlled Trials
A crucial task for a randomized controlled trial (RCT) is to specify a
statistical method that can yield an efficient estimator and powerful test for
the treatment effect. A novel and effective strategy to obtain efficient and
powerful treatment effect inferences is to incorporate predictions from
generative artificial intelligence (AI) algorithms into covariate adjustment
for the regression analysis of a RCT. Training a generative AI algorithm on
historical control data enables one to construct a digital twin generator (DTG)
for RCT participants, which utilizes a participant's baseline covariates to
generate a probability distribution for their potential control outcome.
Summaries of the probability distribution from the DTG are highly predictive of
the trial outcome, and adjusting for these features via regression can thus
improve the quality of treatment effect inferences, while satisfying regulatory
guidelines on statistical analyses, for a RCT. However, a critical assumption
in this strategy is homoskedasticity, or constant variance of the outcome
conditional on the covariates. In the case of heteroskedasticity, existing
covariate adjustment methods yield inefficient estimators and underpowered
tests. We propose to address heteroskedasticity via a weighted prognostic
covariate adjustment methodology (Weighted PROCOVA) that adjusts for both the
mean and variance of the regression model using information obtained from the
DTG. We prove that our method yields unbiased treatment effect estimators, and
demonstrate via comprehensive simulation studies and case studies from
Alzheimer's disease that it can reduce the variance of the treatment effect
estimator, maintain the Type I error rate, and increase the power of the test
for the treatment effect from 80% to 85%~90% when the variances from the DTG
can explain 5%~10% of the variation in the RCT participants' outcomes.Comment: 49 pages, 6 figures, 12 table
- …