Algorithmic paradigms for stability-based cluster validity and model selection statistical methods, with applications to microarray data analysis

AbstractThe advent of high throughput technologies, in particular microarrays, for biological research has revived interest in clustering, resulting in a plethora of new clustering algorithms. However, model selection, i.e., the identification of the correct number of clusters in a dataset, has received relatively little attention. Indeed, although central for statistics, its difficulty is also well known. Fortunately, a few novel techniques for model selection, representing a sharp departure from previous ones in statistics, have been proposed and gained prominence for microarray data analysis. Among those, the stability-based methods are the most robust and best performing in terms of prediction, but the slowest in terms of time. It is very unfortunate that as fascinating and classic an area of statistics as model selection, with important practical applications, has received very little attention in terms of algorithmic design and engineering. In this paper, in order to partially fill this gap, we make the following contributions: (A) the first general algorithmic paradigm for stability-based methods for model selection; (B) reductions showing that all of the known methods in this class are an instance of the proposed paradigm; (C) a novel algorithmic paradigm for the class of stability-based methods for cluster validity, i.e., methods assessing how statistically significant is a given clustering solution; (D) a general algorithmic paradigm that describes heuristic and very effective speed-ups known in the literature for stability-based model selection methods.Since the performance evaluation of model selection algorithms is mainly experimental, we offer, for completeness and without even attempting to be exhaustive, a representative synopsis of known experimental benchmarking results that highlight the ability of stability-based methods for model selection and the computational resources that they require for the task. As a whole, the contributions of this paper generalize in several respects reference methodologies in statistics and show that algorithmic approaches can yield deep methodological insights into this area, in addition to practical computational procedures

Enhancing Next-Generation Sequencing-Guided Cancer Care Through Cognitive Computing

Background: Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human “molecular tumor boards” (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB. Materials and Methods: One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis. Results: Using a WfG-curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker-selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case. Conclusion: These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up-to-date availability of clinical trials. Implications for Practice: The results of this study demonstrate that the interpretation and actionability of somatic next-generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost-effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data

The intrinsic combinatorial organization and information theoretic content of a sequence are correlated to the DNA encoded nucleosome organization of eukaryotic genomes

Motivation: Thanks to research spanning nearly 30 years, two major models have emerged that account for nucleosome organization in chromatin: statistical and sequence specific. The first is based on elegant, easy to compute, closed-form mathematical formulas that make no assumptions of the physical and chemical properties of the underlying DNA sequence. Moreover, they need no training on the data for their computation. The latter is based on some sequence regularities but, as opposed to the statistical model, it lacks the same type of closed-form formulas that, in this case, should be based on the DNA sequence only. Results: We contribute to close this important methodological gap between the two models by providing three very simple formulas for the sequence specific one. They are all based on well-known formulas in Computer Science and Bioinformatics, and they give different quantifications of how complex a sequence is. In view of how remarkably well they perform, it is very surprising that measures of sequence complexity have not even been considered as candidates to close the mentioned gap. We provide experimental evidence that the intrinsic level of combinatorial organization and information-theoretic content of subsequences within a genome are strongly correlated to the level of DNA encoded nucleosome organization discovered by Kaplan et al. Our results establish an important connection between the intrinsic complexity of subsequences in a genome and the intrinsic, i.e. DNA encoded, nucleosome organization of eukaryotic genomes. It is a first step towards a mathematical characterization of this latter 'encoding'. Supplementary information: Supplementary data are available at Bioinformatics onlin

Stability-Based Model Selection for High Throughput Genomic Data: An Algorithmic Paradigm

Clustering is one of the most well known activities in scien- tific investigation and the object of research in many disciplines, ranging from Statistics to Computer Science. In this beautiful area, one of the most difficult challenges is the model selection problem, i.e., the identifi- cation of the correct number of clusters in a dataset. In the last decade, a few novel techniques for model selection, representing a sharp departure from previous ones in statistics, have been proposed and gained promi- nence for microarray data analysis. Among those, the stability-based methods are the most robust and best performing in terms of predic- tion, but the slowest in terms of time. Unfortunately, this fascinating and classic area of statistics as model selection, with important practical applications, has received very little attention in terms of algorithmic design and engineering. In this paper, in order to partially fill this gap, we highlight: (A) the first general algorithmic paradigm for stability- based methods for model selection; (B) a novel algorithmic paradigm for the class of stability-based methods for cluster validity, i.e., methods assessing how statistically significant is a given clustering solution; (C) a general algorithmic paradigm that describes heuristic and very effective speed-ups known in the Literature for stability-based model selection methods

Textual data compression in computational biology: Algorithmic techniques.

In a recent review [R. Giancarlo, D. Scaturro, F. Utro, Textual data compression in computational biology: a synopsis, Bioinformatics 25 (2009) 1575–1586] the first systematic organization and presentation of the impact of textual data compression for the analysis of biological data has been given. Its main focus was on a systematic presentation of the key areas of bioinformatics and computational biology where compression has been used together with a technical presentation of how well-known notions from information theory have been adapted to successfully work on biological data. Rather surprisingly, the use of data compression is pervasive in computational biology. Starting from that one, the focus of this companion review is on the computational methods involved in the use of data compression in computational biology. Indeed, although one would expect ad hoc adaptation of compression techniques to work on biological data, unifying and homogeneous algorithmic approaches are emerging. Moreover, given that experiments based on parallel sequencing are the future for biological research, data compression techniques are among a handful of candidates that seem able, successfully, to deal with the deluge of sequence data they produce; although, until now, only in terms of storage and indexing, with the analysis still being a challenge. Therefore, the two reviews, complementing each other, are perceived to be a useful starting point for computer scientists to get acquainted with many of the computational challenges coming from computational biology in which core ideas of the information sciences are already having a substantial impact

Bayesian versus data driven model selection for microarray data

Clustering is one of the most well known activities in scientific investigation and the object of research in many disciplines, ranging from Statistics to Computer Science. In this beautiful area, one of the most difficult challenges is a particular instance of the model selection problem, i.e., the identification of the correct number of clusters in a dataset. In what follows, for ease of reference, we refer to that instance still as model selection. It is an important part of any statistical analysis. The techniques used for solving it are mainly either Bayesian or data-driven, and are both based on internal knowledge. That is, they use information obtained by processing the input data. Although both techniques have been evaluated in the realm of microarray data analysis, their merits (relative to each other) has not been assessed. Here we will fill this gap in the literature by comparing three Bayesians versus several state of the art data-driven model selection methods. Our results show that, although in some cases Bayesian methods guarantee good results, they are not able to compete in terms of ability to predict the correct number of clusters in a dataset with the data-driven method

Compressive biological sequence analysis and archival in the era of high-throughput sequencing technologies

High-throughput sequencing technologies produce large collections of data, mainly DNA sequences with additional information, requiring the design of efficient and effective methodologies for both their compression and storage. In this context, we first provide a classification of the main techniques that have been proposed, according to three specific research directions that have emerged from the literature and, for each, we provide an overview of the current techniques. Finally, to make this review useful to researchers and technicians applying the existing software and tools, we include a synopsis of the main characteristics of the described approaches, including details on their implementation and availability. Performance of the various methods is also highlighted, although the state of the art does not lend itself to a consistent and coherent comparison among all the methods presented here