Rejoinder: Quantifying the Fraction of Missing Information for Hypothesis Testing in Statistical and Genetic Studies

Rejoinder to "Quantifying the Fraction of Missing Information for Hypothesis Testing in Statistical and Genetic Studies" [arXiv:1102.2774]Comment: Published in at http://dx.doi.org/10.1214/08-STS244REJ the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Quantifying the Fraction of Missing Information for Hypothesis Testing in Statistical and Genetic Studies

Many practical studies rely on hypothesis testing procedures applied to data sets with missing information. An important part of the analysis is to determine the impact of the missing data on the performance of the test, and this can be done by properly quantifying the relative (to complete data) amount of available information. The problem is directly motivated by applications to studies, such as linkage analyses and haplotype-based association projects, designed to identify genetic contributions to complex diseases. In the genetic studies the relative information measures are needed for the experimental design, technology comparison, interpretation of the data, and for understanding the behavior of some of the inference tools. The central difficulties in constructing such information measures arise from the multiple, and sometimes conflicting, aims in practice. For large samples, we show that a satisfactory, likelihood-based general solution exists by using appropriate forms of the relative Kullback--Leibler information, and that the proposed measures are computationally inexpensive given the maximized likelihoods with the observed data. Two measures are introduced, under the null and alternative hypothesis respectively. We exemplify the measures on data coming from mapping studies on the inflammatory bowel disease and diabetes. For small-sample problems, which appear rather frequently in practice and sometimes in disguised forms (e.g., measuring individual contributions to a large study), the robust Bayesian approach holds great promise, though the choice of a general-purpose "default prior" is a very challenging problem.Comment: Published in at http://dx.doi.org/10.1214/07-STS244 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Unsupervised empirical Bayesian multiple testing with external covariates

In an empirical Bayesian setting, we provide a new multiple testing method, useful when an additional covariate is available, that influences the probability of each null hypothesis being true. We measure the posterior significance of each test conditionally on the covariate and the data, leading to greater power. Using covariate-based prior information in an unsupervised fashion, we produce a list of significant hypotheses which differs in length and order from the list obtained by methods not taking covariate-information into account. Covariate-modulated posterior probabilities of each null hypothesis are estimated using a fast approximate algorithm. The new method is applied to expression quantitative trait loci (eQTL) data.Comment: Published in at http://dx.doi.org/10.1214/08-AOAS158 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Localization of a gene for migraine without aura to chromosome 4q21.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldMigraine is a common form of headache and has a significant genetic component. Here, we report linkage results from a study in Iceland of migraine without aura (MO). The study group comprised patients with migraine recruited by neurologists and from the registry of the Icelandic Migraine Society, as well as through the use of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses were made and confirmed using diagnostic criteria established by the International Headache Society. A genome-wide scan with multipoint allele-sharing methods was performed on 289 patients suffering from MO. Linkage was observed to a locus on chromosome 4q21 (LOD=2.05; P=.001). The locus reported here overlaps a locus (MGR1) reported elsewhere for patients with migraine with aura (MA) in the Finnish population. This replication of the MGR1 locus in families with MO indicates that the gene we have mapped may contribute to both MA and MO. Further analysis indicates that the linkage evidence improves for affected females and, especially, with a slightly relaxed definition of MO (LOD=4.08; P=7.2 x 10(-6))

Chitosan-Cellulose Composite for Wound Dressing Material. Part 2. Antimicrobial Activity, Blood Absorption Ability, and Biocompatibility

Chitosan (CS), a polysaccharide derived from chitin, the second most abundant polysaccharide, is widely used in the medical world because of its natural and nontoxic properties and its innate ability for antibacterial and hemostasis effects. In this study, the novel composites containing CS and cellulose (CEL) (i.e., [CEL + CS]), which we have previously synthesized using a green and totally recyclable method, were investigated for their antimicrobial activity, absorption of anticoagulated whole blood, anti-inflammatory activity through the reduction of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and the biocompatibility with human fibroblasts. The [CEL + CS] composites were found to inhibit the growth of both Gram positive and negative micro-organisms. For examples, the regenerated 100% lyophilized chitosan material was found to reduce growth of Escherichia coli (ATCC 8739 and vancomycin resistant Enterococcus faecalis (ATCC 51299) by 78, 36, and 64%, respectively. The composites are nontoxic to fibroblasts; that is, fibroblasts, which are critical to the formation of connective tissue matrix were found to grow and proliferate in the presence of the composites. They effectively absorb blood, and at the same rate and volume as commercially available wound dressings. The composites, in both air-dried and lyophilized forms, significantly inhibit the production of TNF-α and IL-6 by stimulated macrophages. These results clearly indicate that the biodegradable, biocompatible and nontoxic [CEL + CS] composites, particularly those dried by lyophilizing, can be effectively used as a material in wound dressings

A direct characterization of human mutation based on microsatellites

Mutations are the raw material of evolution, but have been difficult to study directly. We report the largest study of new mutations to date: 2,058 germline changes discovered by analyzing 85,289 Icelanders at 2,477 microsatellites. The paternal-to-maternal mutation rate ratio is 3.3, and the rate in fathers doubles from age 20 to 58 whereas there is no association with age in mothers. Longer microsatellite alleles are more mutagenic and tend to decrease in length, whereas the opposite is seen for shorter alleles. We use these empirical observations to build a model that we apply to individuals for whom we have both genome sequence and microsatellite data, allowing us to estimate key parameters of evolution without calibration to the fossil record. We infer that the sequence mutation rate is 1.4–2.3×10−8 per base pair per generation (90% credible interval), and that human-chimpanzee speciation occurred 3.7–6.6 million years ago

Chemosensory modulation of neural circuits for sodium appetite

Sodium is the main cation in the extracellular fluid and it regulates various physiological functions. Depletion of sodium in the body increases the hedonic value of sodium taste, which drives animals towards sodium consumption. By contrast, oral sodium detection rapidly quenches sodium appetite, suggesting that taste signals have a central role in sodium appetite and its satiation. Nevertheless, the neural mechanisms of chemosensory-based appetite regulation remain poorly understood. Here we identify genetically defined neural circuits in mice that control sodium intake by integrating chemosensory and internal depletion signals. We show that a subset of excitatory neurons in the pre-locus coeruleus express prodynorphin, and that these neurons are a critical neural substrate for sodium-intake behaviour. Acute stimulation of this population triggered robust ingestion of sodium even from rock salt, while evoking aversive signals. Inhibition of the same neurons reduced sodium consumption selectively. We further demonstrate that the oral detection of sodium rapidly suppresses these sodium-appetite neurons. Simultaneous in vivo optical recording and gastric infusion revealed that sodium taste—but not sodium ingestion per se—is required for the acute modulation of neurons in the pre-locus coeruleus that express prodynorphin, and for satiation of sodium appetite. Moreover, retrograde-virus tracing showed that sensory modulation is in part mediated by specific GABA (γ-aminobutyric acid)-producing neurons in the bed nucleus of the stria terminalis. This inhibitory neural population is activated by sodium ingestion, and sends rapid inhibitory signals to sodium-appetite neurons. Together, this study reveals a neural architecture that integrates chemosensory signals and the internal need to maintain sodium balance

Support for involvement of the AHI1 locus in schizophrenia

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldRecently, markers in the Abelson Helper Integration Site 1 (AHI1) region were shown to be associated with schizophrenia in a family sample of Israeli-Arabs. Here, we report a study evaluating the relevance of the AHI1 region to schizophrenia in an Icelandic sample. Seven markers shown to confer risk in the previous report were typed in 608 patients diagnosed with broad schizophrenia and 1,504 controls. Odds ratios for the overtransmitted alleles in the Israeli-Arab families ranged from 1.15 to 1.29 in the Icelandic sample. After Bonferroni correction for the seven markers tested, two markers were significantly associated with schizophrenia. Thus, our results are in general agreement with the previous report, with the strongest association signal observed in a region upstream of the AHI1 gene

Association of neuregulin 1 with schizophrenia confirmed in a Scottish population

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldRecently, we identified neuregulin 1 (NRG1) as a susceptibility gene for schizophrenia in the Icelandic population, by a combined linkage and association approach. Here, we report the first study evaluating the relevance of NRG1 to schizophrenia in a population outside Iceland. Markers representing a core at-risk haplotype found in Icelanders at the 5' end of the NRG1 gene were genotyped in 609 unrelated Scottish patients and 618 unrelated Scottish control individuals. This haplotype consisted of five SNP markers and two microsatellites, which all appear to be in strong linkage disequilibrium. For the Scottish patients and control subjects, haplotype frequencies were estimated by maximum likelihood, using the expectation-maximization algorithm. The frequency of the seven-marker haplotype among the Scottish patients was significantly greater than that among the control subjects (10.2% vs. 5.9%, P=.00031). The estimated risk ratio was 1.8, which is in keeping with our report of unrelated Icelandic patients (2.1). Three of the seven markers in the haplotype gave single-point P values ranging from .000064 to .0021 for the allele contributing to the at-risk haplotype. This direct replication of haplotype association in a second population further implicates NRG1 as a factor that contributes to the etiology of schizophrenia

Lack of benefits for prevention of cardiovascular disease with aspirin therapy in type 2 diabetic patients - a longitudinal observational study

<p>Abstract</p> <p>Background</p> <p>The risk-benefit ratio of aspirin therapy in prevention of cardiovascular disease (CVD) remains contentious, especially in type 2 diabetes. This study examined the benefit and harm of low-dose aspirin (daily dose < 300 mg) in patients with type 2 diabetes.</p> <p>Methods</p> <p>This is a longitudinal observational study with primary and secondary prevention cohorts based on history of CVD at enrolment. We compared the occurrence of primary composite (non-fatal myocardial infarction or stroke and vascular death) and secondary endpoints (upper GI bleeding and haemorrhagic stroke) between aspirin users and non-users between January 1995 and July 2005.</p> <p>Results</p> <p>Of the 6,454 patients (mean follow-up: median [IQR]: 4.7 [4.4] years), usage of aspirin was 18% (n = 1,034) in the primary prevention cohort (n = 5731) and 81% (n = 585) in the secondary prevention cohort (n = 723). After adjustment for covariates, in the primary prevention cohort, aspirin use was associated with a hazard-ratio of 2.07 (95% CI: 1.66, 2.59, p < 0.001) for primary endpoint. There was no difference in CVD event rate in the secondary prevention cohort. Overall, aspirin use was associated with a hazard-ratio of 2.2 (1.53, 3.15, p < 0.001) of GI bleeding and 1.71 (1.00, 2.95, p = 0.051) of haemorrhagic stroke. The absolute risk of aspirin-related GI bleeding was 10.7 events per 1,000 person-years of treatment.</p> <p>Conclusion</p> <p>In Chinese type 2 diabetic patients, low dose aspirin was associated with a paradoxical increase in CVD risk in primary prevention and did not confer benefits in secondary prevention. In addition, the risk of GI bleeding in aspirin users was rather high.</p