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Chiara Sabatti

Publications and source records attributed to Chiara Sabatti.

23 records · Page 2Linked to original sources

SLOPE - Adaptive variable selection via convex optimization

We introduce a new estimator for the vector of coefficients $β$ in the linear model $y=Xβ+z$, where $X$ has dimensions $n\times p$ with $p$ possibly larger than $n$. SLOPE, short for Sorted L-One Penalized Estimation, is the solution to \[\min_{b\in\mathbb{R}^p}\frac{1}{2}\Vert y-Xb\Vert _{\ell_2}^2+λ_1\vert b\vert _{(1)}+λ_2\vert b\vert_{(2)}+\cdots+λ_p\vert b\vert_{(p)},\] where $λ_1\geλ_2\ge\cdots\geλ_p\ge0$ and $\vert b\vert_{(1)}\ge\vert b\vert_{(2)}\ge\cdots\ge\vert b\vert_{(p)}$ are the decreasing absolute values of the entries of $b$. This is a convex program and we demonstrate a solution algorithm whose computational complexity is roughly comparable to that of classical $\ell_1$ procedures such as the Lasso. Here, the regularizer is a sorted $\ell_1$ norm, which penalizes the regression coefficients according to their rank: the higher the rank - that is, stronger the signal - the larger the penalty. This is similar to the Benjamini and Hochberg [J. Roy. Statist. Soc. Ser. B 57 (1995) 289-300] procedure (BH) which compares more significant $p$-values with more stringent thresholds. One notable choice of the sequence $\{λ_i\}$ is given by the BH critical values $λ_{\mathrm {BH}}(i)=z(1-i\cdot q/2p)$, where $q\in(0,1)$ and $z(α)$ is the quantile of a standard normal distribution. SLOPE aims to provide finite sample guarantees on the selected model; of special interest is the false discovery rate (FDR), defined as the expected proportion of irrelevant regressors among all selected predictors. Under orthogonal designs, SLOPE with $λ_{\mathrm{BH}}$ provably controls FDR at level $q$. Moreover, it also appears to have appreciable inferential properties under more general designs $X$ while having substantial power, as demonstrated in a series of experiments running on both simulated and real data.

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Many Phenotypes without Many False Discoveries: Error Controlling Strategies for Multi-Traits Association Studies

The genetic basis of multiple phenotypes such as gene expression, metabolite levels, or imaging features is often investigated by testing a large collection of hypotheses, probing the existence of association between each of the traits and hundreds of thousands of genotyped variants. Appropriate multiplicity adjustment is crucial to guarantee replicability of findings, and False Discovery Rate (FDR) is frequently adopted as a measure of global error. In the interest of interpretability, results are often summarized so that reporting focuses on variants discovered to be associated to some phenotypes. We show that applying FDR-controlling procedures on the entire collection of hypotheses fails to control the rate of false discovery of associated variants as well as the average rate of false discovery of phenotypes influenced by such variants. We propose a simple hierarchical testing procedure which allows control of both these error rates and provides a more reliable basis for the identification of variants with functional effects. We demonstrate the utility of this approach through simulation studies comparing various error rates and measures of power for genetic association studies of multiple traits. Finally, we apply the proposed method to identify genetic variants which impact flowering phenotypes in Arabdopsis thaliana, expanding the set of discoveries.

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Reconstructing DNA copy number by joint segmentation of multiple sequences

The variation in DNA copy number carries information on the modalities of genome evolution and misregulation of DNA replication in cancer cells; its study can be helpful to localize tumor suppressor genes, distinguish different populations of cancerous cell, as well identify genomic variations responsible for disease phenotypes. A number of different high throughput technologies can be used to identify copy number variable sites, and the literature documents multiple effective algorithms. We focus here on the specific problem of detecting regions where variation in copy number is relatively common in the sample at hand: this encompasses the cases of copy number polymorphisms, related samples, technical replicates, and cancerous sub-populations from the same individual. We present an algorithm based on regularization approaches with significant computational advantages and competitive accuracy. We illustrate its applicability with simulated and real data sets.

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Reconstructing DNA copy number by penalized estimation and imputation

Recent advances in genomics have underscored the surprising ubiquity of DNA copy number variation (CNV). Fortunately, modern genotyping platforms also detect CNVs with fairly high reliability. Hidden Markov models and algorithms have played a dominant role in the interpretation of CNV data. Here we explore CNV reconstruction via estimation with a fused-lasso penalty as suggested by Tibshirani and Wang [Biostatistics 9 (2008) 18--29]. We mount a fresh attack on this difficult optimization problem by the following: (a) changing the penalty terms slightly by substituting a smooth approximation to the absolute value function, (b) designing and implementing a new MM (majorization--minimization) algorithm, and (c) applying a fast version of Newton's method to jointly update all model parameters. Together these changes enable us to minimize the fused-lasso criterion in a highly effective way. We also reframe the reconstruction problem in terms of imputation via discrete optimization. This approach is easier and more accurate than parameter estimation because it relies on the fact that only a handful of possible copy number states exist at each SNP. The dynamic programming framework has the added bonus of exploiting information that the current fused-lasso approach ignores. The accuracy of our imputations is comparable to that of hidden Markov models at a substantially lower computational cost.

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Sparse regulatory networks

In many organisms the expression levels of each gene are controlled by the activation levels of known "Transcription Factors" (TF). A problem of considerable interest is that of estimating the "Transcription Regulation Networks" (TRN) relating the TFs and genes. While the expression levels of genes can be observed, the activation levels of the corresponding TFs are usually unknown, greatly increasing the difficulty of the problem. Based on previous experimental work, it is often the case that partial information about the TRN is available. For example, certain TFs may be known to regulate a given gene or in other cases a connection may be predicted with a certain probability. In general, the biology of the problem indicates there will be very few connections between TFs and genes. Several methods have been proposed for estimating TRNs. However, they all suffer from problems such as unrealistic assumptions about prior knowledge of the network structure or computational limitations. We propose a new approach that can directly utilize prior information about the network structure in conjunction with observed gene expression data to estimate the TRN. Our approach uses $L_1$ penalties on the network to ensure a sparse structure. This has the advantage of being computationally efficient as well as making many fewer assumptions about the network structure. We use our methodology to construct the TRN for E. coli and show that the estimate is biologically sensible and compares favorably with previous estimates.

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