SUMMARY The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.

/pdf/controlling-the-false-discovery-rate-a-practical-and-431ouqffk6.pdf

Controlling the false discovery rate: a practical and powerful approach to multiple testing

In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html
 .

/pdf/moderated-estimation-of-fold-change-and-dispersion-for-rna-3ywnbkcan0.pdf

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

/pdf/gene-set-enrichment-analysis-a-knowledge-based-approach-for-mbpti6qljw.pdf

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.

http://ibgwww.colorado.edu/cdrom2009/ScriptsA/purcell/GWAS/boulder_09_plink_intro.pdf

PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses

Typically, locomotion has been studied by restricting the animal’s path and/or speed, focusing on stride and step kinematics. Here we incorporate measurements of the legs and trunk in the support and swing phases, during trotting with various speeds and curvatures. This paradigm releases the animal from the confines of the treadmill and runway into the open space. The diagonal step, a new unit of locomotion, is defined by regarding the line between the two supporting diagonal legs as a frame of reference for the description of the dynamics of the virtual line between the two swinging diagonal legs. This analysis reveals that during free trotting the mouse uses three types of steps: fixating, opening, and closing steps. During progression along a straight path, the mouse uses fixating steps, in which the swinging diagonal maintains a fixed direction, landing on the supporting foreleg; during progression along a curved path the mouse uses opening and closing steps alternately. If two steps of the same type are performed sequentially, they engender an abrupt change of direction. Our results reveal how steering with the swinging diagonal, while using a virtually bipedal gait, engenders the whole repertoire of free-trotting behavior.

Coordination of steering in a free-trotting quadruped.

Rats injected with 5.0 mg/kg (+)-amphetamine perform, at one stage of the drug's influence, rhythmic side-to-side head movements while walking. This makes them an interesting preparation for investigating how stereotyped motor patterns emerge from the coordination of periodic movements. We report here such a pattern we have isolated: the left foreleg and the right hindleg land on the ground as the head reaches the peak of its movement to the right, and vice versa (contra-lateral pattern). We show that this pattern can be explained as a stable equilibrium in a simple, nonlinear dynamical model, similar to models developed for tapping with both hands in human subjects. The model also accounts for sequences of behavior that are not in the contra-lateral pattern, explaining them as a flow of the system back towards the stable equilibrium after a disturbance.

Motor patterns that constitute the building blocks of unconstrained behavior are often defined as fixed phase relations between movements of the parts of the body. This study applies the paradigm of Dynamic Pattern Generation to free (unconstrained) behavior: motor patterns are defined as stable equilibria in dynamical systems, assembled by mutual influence of concurrent movements. Our findings suggest that this definition is more powerful for the description of free behavior. The amphetamine-treated rat is a useful preparation for investigating this notion in an unconstrained animal whose behavior is still not as complex and variable as that of the normal animal.

Coordination of side-to-side head movements and walking in amphetamine-treated rats: a stereotyped motor pattern as a stable equilibrium in a dynamical system

In many large multiple testing problems the hypotheses are divided into families. Given the data, families with evidence for true discoveries are selected, and hypotheses within them are tested. Neither controlling the error-rate in each family separately nor controlling the error-rate over all hypotheses together can assure that an error-rate is

Adjusting for selection bias in testing multiple families of hypotheses

The interaction between a low-dose cholinesterase inhibitor, pyridostigmine (PYR), and atropine was investigated by spectral analysis of heart rate fluctuations in eight healthy humans. Each subject was given increasing boluses of IV atropine during treatment with PYR (30 mg.3/day) or placebo. PYR attenuated the bimodal dose-dependent changes in the respiratory peak (which respresents the parasympathetic control) in response to atropine. We suggest that spectral analysis can be used for quantifying the complex dose-dependent cholinergic agonist-antagonist interactions, and may help to disclose an asymptomatic low-dose intoxication with acetylcholinesterase inhibitors.

Modulation of the dose-dependent effects of atropine by low-dose pyridostigmine: quantification by spectral analysis of heart rate fluctuations in healthy human beings.

This paper suggests a GIS-based methodology for the investigation of the extent to which the inhabitants of a representative sample of city residents perceives itself as living in socially constituted neighborhood territories. We ask residents about the relevancy of the neighborhood as a social unit and to delineate their neighborhood boundaries. We then define these delineations as polygons in GIS, measuring the tendency of neighbors to define merging territorial bases for their neighborhoods. Three possible patterns are identified: (1) lack of perceived boundaries resulting from the irrelevancy of the neighborhood, (2) personal senses of localities that do not merge into communal territories by immediate neighbors—in this case we conclude that residents experience some sense of locality but they do not share any common sense of neighborhood—and (3) the tendency of residents' delineations to merge with those of their neighbors demonstrating, by thus, the social constitution of communal sense of neighborh...

Yoav Benjamini

Papers

Coordination of steering in a free-trotting quadruped.

Coordination of side-to-side head movements and walking in amphetamine-treated rats: a stereotyped motor pattern as a stable equilibrium in a dynamical system

Adjusting for selection bias in testing multiple families of hypotheses

Modulation of the dose-dependent effects of atropine by low-dose pyridostigmine: quantification by spectral analysis of heart rate fluctuations in healthy human beings.

Research Note: Neighborhoods as Territorial Units: The Case of Tel Aviv-Jaffa