A frequentist framework of inductive reasoning

Reacting against the limitation of statistics to decision procedures, R. A. Fisher proposed for inductive reasoning the use of the fiducial distribution, a parameter-space distribution of epistemological probability transferred directly from limiting relative frequencies rather than computed according to the Bayes update rule. The proposal is developed as follows using the confidence measure of a scalar parameter of interest. (With the restriction to one-dimensional parameter space, a confidence measure is essentially a fiducial probability distribution free of complications involving ancillary statistics.) A betting game establishes a sense in which confidence measures are the only reliable inferential probability distributions. The equality between the probabilities encoded in a confidence measure and the coverage rates of the corresponding confidence intervals ensures that the measure's rule for assigning confidence levels to hypotheses is uniquely minimax in the game. Although a confidence measure can be computed without any prior distribution, previous knowledge can be incorporated into confidence-based reasoning. To adjust a p-value or confidence interval for prior information, the confidence measure from the observed data can be combined with one or more independent confidence measures representing previous agent opinion. (The former confidence measure may correspond to a posterior distribution with frequentist matching of coverage probabilities.) The representation of subjective knowledge in terms of confidence measures rather than prior probability distributions preserves approximate frequentist validity.Comment: major revisio

ACE inhibition attenuates uremia-induced aortic valve thickening in a novel mouse model

<p>Abstract</p> <p>Background</p> <p>We examined whether impaired renal function causes thickening of the aortic valve leaflets in hyperlipidemic apoE-knockout (apoE^-/-) mice, and whether the putative effect on the aortic valves could be prevented by inhibiting the angiotensin-converting enzyme (ACE) with enalapril.</p> <p>Methods</p> <p>Thickening of the aortic valve leaflets in apoE^-/-mice was induced by producing mild or moderate chronic renal failure resulting from unilateral nephrectomy (1/2 NX, n = 18) or subtotal nephrectomy (5/6 NX, n = 22), respectively. Additionally, the 5/6 NX mice were randomized to no treatment (n = 8) or enalapril treatment (n = 13). The maximal thickness of each leaflet was measured from histological sections of the aortic roots.</p> <p>Results</p> <p>Leaflet thickness was significantly greater in the 5/6 NX mice than in the 1/2 NX mice (P = 0.030) or the unoperated mice (P = 0.003). The 5/6 NX mice treated with enalapril had significantly thinner leaflets than did the untreated 5/6 NX mice (P = 0.014).</p> <p>Conclusion</p> <p>Moderate uremia causes thickening of the aortic valves in apoE^-/-mice, which can be attenuated by ACE inhibition. The nephrectomized apoE^-/-mouse constitutes a new model for investigating the mechanisms of uremia-induced aortic valve disease, and also provides an opportunity to study its pharmacologic prevention.</p

Outcome of coronary plaque burden: a 10-year follow-up of aggressive medical management

<p>Abstract</p> <p>Background</p> <p>The effect of aggressive medical therapy on quantitative coronary plaque burden is not generally known, especially in ethnic Chinese.</p> <p>Aims</p> <p>We reasoned that Cardiac CT could conveniently quantify early coronary atherosclerosis in our patient population, and hypothesized that serial observation could differentiate the efficacy of aggressive medical therapy regarding progression and regression of the atherosclerotic process, as well as evaluating the additional impact of life-style modification and the relative effects of the application of statin therapy.</p> <p>Methods</p> <p>We employed a standardized Cardiac CT protocol to serially scan 113 westernized Hong Kong Chinese individuals (64 men and 49 women) with Chest Pain and positive coronary risk factors. In all cases included for this serial investigation, subsequent evaluation showed no significantly-obstructive coronary disease by functional studies and angiography. After stringent risk factor modification, including aggressive statin therapy to achieve LDL-cholesterol lowering conforming to N.C.E.P. ATP III guidelines, serial CT scans were performed 1-12 years apart for changes in coronary artery calcification (CAC), using the Agatston Score (AS) for quantification.</p> <p>Results</p> <p>At baseline, the mean AS was 1413.6 for males (mean age 54.4 years) and 2293.3 for females (mean age 62.4 years). The average increase of AS in the entire study population was 24% per year, contrasting with 16.4% per year on strict risk factor modification plus statin therapy, as opposed to 33.2% per year for historical control patients (p < 0.001). Additionally, 20.4% of the 113 patients demonstrated decreasing calcium scores. Medical therapy also yielded a remarkably low adverse event rate during the follow-up period --- 2 deaths, 2 strokes and only 1 case requiring PCI.</p> <p>Conclusions</p> <p>This study revealed that aggressive medical therapy can positively influence coronary plaque aiding in serial regression of calcium scores.</p

Comprehensive Gene-Based Association Study of a Chromosome 20 Linked Region Implicates Novel Risk Loci for Depressive Symptoms in Psychotic Illness

Background Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants. Methods We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus. Results While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (PempP-value and truncated-product methods, respectively. Conclusions Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci

Haplotype Analysis Improved Evidence for Candidate Genes for Intramuscular Fat Percentage from a Genome Wide Association Study of Cattle

In genome wide association studies (GWAS), haplotype analyses of SNP data are neglected in favour of single point analysis of associations. In a recent GWAS, we found that none of the known candidate genes for intramuscular fat (IMF) had been identified. In this study, data from the GWAS for these candidate genes were re-analysed as haplotypes. First, we confirmed that the methodology would find evidence for association between haplotypes in candidate genes of the calpain-calpastatin complex and musculus longissimus lumborum peak force (LLPF), because these genes had been confirmed through single point analysis in the GWAS. Then, for intramuscular fat percent (IMF), we found significant partial haplotype substitution effects for the genes ADIPOQ and CXCR4, as well as suggestive associations to the genes CEBPA, FASN, and CAPN1. Haplotypes for these genes explained 80% more of the phenotypic variance compared to the best single SNP. For some genes the analyses suggested that there was more than one causative mutation in some genes, or confirmed that some causative mutations are limited to particular subgroups of a species. Fitting the SNPs and their interactions simultaneously explained a similar amount of the phenotypic variance compared to haplotype analyses. Haplotype analysis is a neglected part of the suite of tools used to analyse GWAS data, would be a useful method to extract more information from these data sets, and may contribute to reducing the missing heritability problem

Donepezil Impairs Memory in Healthy Older Subjects: Behavioural, EEG and Simultaneous EEG/fMRI Biomarkers

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement