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J Am Med Inform Assoc. 2009 Nov-Dec; 16(6): 759–767.
PMCID: PMC3002128

Large Datasets in Biomedicine: A Discussion of Salient Analytic Issues

Anshu Sinha, a George Hripcsak, MD, MS, a and Marianthi Markatou, PhD b , *

Abstract

Advances in high-throughput and mass-storage technologies have led to an information explosion in both biology and medicine, presenting novel challenges for analysis and modeling. With regards to multivariate analysis techniques such as clustering, classification, and regression, large datasets present unique and often misunderstood challenges. The authors' goal is to provide a discussion of the salient problems encountered in the analysis of large datasets as they relate to modeling and inference to inform a principled and generalizable analysis and highlight the interdisciplinary nature of these challenges. The authors present a detailed study of germane issues including high dimensionality, multiple testing, scientific significance, dependence, information measurement, and information management with a focus on appropriate methodologies available to address these concerns. A firm understanding of the challenges and statistical technology involved ultimately contributes to better science. The authors further suggest that the community consider facilitating discussion through interdisciplinary panels, invited papers and curriculum enhancement to establish guidelines for analysis and reporting.

Introduction

Advances in high-throughput and mass-storage technologies have led to an information explosion in both biology and medicine, improving and changing the face of health care, as well as presenting unique and complex challenges for analysis, modeling and inference. In the clinical arena, the twin objectives of identifying targets to minimize consumption of resources and improving quality of care drive the collection of large amounts of data. Similarly, in biology, describing the connection between genome, transcriptome, proteome, and phenome is fundamentally a problem of modeling biological information processes, involving both experimental and sequence information for an enormous number of factors. With regard to multivariate inferential techniques such as clustering, classification, and regression, many of these large datasets present unique and often misunderstood challenges. Salient issues discussed here are high dimensionality, multiple testing, dependence, scientific significance, information measurement, and information management.

Kettenring (2008) 1 reviewed several hundred papers in some detail as part of a comprehensive investigation into the practice of cluster analysis. Notably, he found that life sciences publications dominated this survey. But more importantly, he concluded that cluster analysis is among the most needed and widely used of the multivariate statistical methodologies and that it is perhaps the one with the most malpractice. He posited that, too often, a researcher's choice of analysis method is dictated and constrained by available software systems because of a lack of knowledge and/or understanding of the available tools and methodologies. These observations can be extended to analysis of large datasets in general. Literature on proper inference analysis and reporting in large datasets is limited, but anecdotally, many researchers concur that issues such as high dimensionality, multiple testing and dependence and their respective solutions, while known to varying degrees within the community, are often misused, misinterpreted, and misunderstood. In other words, there is a large gap between typical practice and best practice in the analysis of large datasets.

A principled analysis of any dataset, small or large, necessitates a firm understanding of the issues and statistical technology involved. Understanding the relevant factors in the analysis of large datasets is an important step in improving study design, structured analysis of data, and generalizability of results. Focus from the community for the development of guidelines for both analysis and the appropriate reporting of analyses performed will aid in this endeavor and ultimately contribute to better science. Here, we provide a discussion of specific problems encountered in the analysis of large datasets as they relate to modeling and inference. In an attempt to improve general understanding, we clearly define these issues, describe them, and present a brief summary of relevant research. This work does not cover general principles of data analysis, but rather those challenges specific to large datasets that affect inference. Some of the issues discussed are general, independent of the size of the data, but exacerbated in large datasets, and some are generated by the size of the data. Although we highlight methodological issues shared across informatics disciplines, we address these issues independently of their domain of application.

We recognize that the topics presented here are not exhaustive. [triangle] puts these issues alongside other inference-related issues to give context. These include sample size, experimental design, data quality, and estimator appropriateness, among others. Again, this is not an exhaustive list, but rather a framework of relevant issues in inference to facilitate discussion and give context. The topics discussed in this article appear in boldface. We have chosen this set because they are especially salient in the era of large data and, more importantly, are often misunderstood. This paper is organized as follows: first, we discuss background and motivations; then we briefly review relevant methodological goals tackled in the inferential analysis of large datasets; next we present a set of salient methodological issues—high dimensionality, multiple testing, statistical significance versus scientific significance, dependence, information measurement and information management—and indicate, where possible, appropriate analytic solutions or further research problems; and finally, we offer conclusions derived from our exploration of the issues.

Table 1
Table 1 A Framework of Issues in the Analysis of Data Sets. Bolded Rows Are Discussed Further in This Paper

Background and Motivations

The term “large dataset” was used academically as early as 1975, when the first conference on large datasets was held (http://portal.acm.org/toc.cfm?id=1282480) discussing database design and management. Some of the characteristics of large datasets, such as high dimensionality (see definition on page 762) and large sample size and their associated issues, were discussed in the statistics literature as early as 1958, 2,3 but the first formal definition of a large dataset was only reported in 1990 in the context of effectiveness research. Large datasets were defined as having the following characteristics: the size of the data is big (106 or greater); it is almost an unbiased representation of the real world, its information content may be unsatisfactory for what a particular researcher has in mind, and it has the ability to be linked with other datasets. 4 In 1995, the National Research Council Committee on Applied and Theoretical Statistics (CATS) gave an informal definition 5 : “a massive dataset is one for which the size, heterogeneity and general complexity cause serious pain for the analyst(s).” Both definitions are linked to potential methodological changes introduced by the nature of large datasets. The sentiment “pain” refers to a number of difficulties, including those formalized in [triangle]. Huber (1994, 1999), 6,7 motivated by the aforementioned changes in analytic methods, introduced this classification of size: 102—tiny, 104—small, 106—medium, 108—large, 1010—huge, 1012—monster. The size of the data impacts the storage mode which can vary from a piece of paper (tiny) to storage silos (monster) and the analytic methods used for information extraction. In many cases, changes in storage size have necessitated new methods for data analysis.

The possible definitions of a large dataset embody different perspectives, reflecting the philosophies of the different scientific fields that deal with these large datasets. The examples given here highlight issues such as size, integration, data heterogeneity, analysis complexity, and computational complexity for which appropriate analytic methods have been and are being developed. Furthermore, depending on the type of analysis and computations that will be performed, salient measures of data and computational complexity for a given dataset can be defined and used to guide decisions associated with the selection of appropriate algorithms for processing and extracting information. 8

In biomedicine, the number of databases has grown explosively over the last 10–20 years. In particular, medical practices and hospitals have implemented electronic systems to collect information on patients treated. In the molecular biology arena, the number of key databases of value to the biological community has grown exponentially from 300 to over 1,000 databases since 2000. 9

These databases themselves are growing at explosive rates. [triangle] shows the cumulative distribution function (CDF) of the growth rate (as a percentage of total current entries) for several important databases in molecular biology and medicine: the Protein Data Bank (PDB), the Entrez Protein database, NCBI's PubMed, and clinical data maintained at Columbia University Medical Center. These examples highlight not only the explosive growth in this field but also the magnitude of complexity in terms of curation, integration, and analysis, making the understanding of large datasets and related methodological issues an important concern for informaticians today.

Figure 1
Cumulative distribution functions (CDFs) for several important informatics resources. CDFs, showing growth rates of: the Entrez Protein database, compiled from a variety of sources including SwissProt, PIR, PRF and PDB; the Protein Data Bank (PDB), a ...

Interdisciplinary Methodological Goals

Our guiding principle is that data are of interest if they can be used to answer important questions. Many analytic goals are common across informatics disciplines, and these goals frame the issues faced when analyzing large datasets. To facilitate discussion, we consider prediction, modeling, and inference as the main methodological goals of a given study. Among the common methods used to achieve these goals are classification, clustering, and regression, which we briefly overview here. 10

Classification, or supervised learning, aims to construct a rule to assign objects to one of a prespecified set of classes based solely on a vector of measurements taken on these objects. The construction of the rule is based on a training set of objects for which the true class is known. Classification can be thought of as predictive modeling, in which the output vector is categorical. Important techniques include logistic regression methods, naive Bayes methods, decision trees, neural networks, Bayesian networks, support vector machines, and hidden Markov models. Pattern recognition applications are often used to aid in image analysis. For example, features of objects in X-rays, such as intensity, perimeter, and area can be used for tumor identification. 11 Classification is also important for clinical decision support systems where symptoms, gene expression, and/or other factors are used as inputs for determination of diagnosis and therapy management. 12,13 More recently, classification techniques have been used for the development of biomarkers showing response to therapy and in building models based on gene expression for disease diagnosis/prognosis.

The purpose of clustering is to find natural groupings in the data through the use of distance metrics. There are many ways to do this, but the most common approach is hierarchical clustering, an unsupervised learning method. Other methods include K-means clustering, principle components based clustering, and self-organizing maps. Developing or reverse engineering networks also falls under the umbrella of clustering. Clustering is often used in latent semantic indexing to find similar documents or terms. 14 Other applications in biomedicine include measuring interpatient distances for improving diagnosis and determining appropriate treatment schedules, 15 in phylogeny, and in microarray data analysis for grouping functionally related genes.

Regression is a statistical analysis tool that quantifies the relationship between a dependent variable and one or more independent variables to depict trends in the data. There are well-known and widely used tools for regression modeling, including linear regression, logistic regression, radial basis function regression, and neural networks, among others. 16 Biomedical applications include decision support, longitudinal analysis of patient data, longitudinal analysis of gene expression, population comparison, and modeling of biological systems.

Interdisciplinary Methodological Issues

The above delineation of analytic tasks is meant to illustrate that, despite the overwhelming variety of phenomena that data can represent, there are some standard forms that data often take, some standard questions we can ask of data, and some standard issues we face. 14 This section offers a discussion of salient issues for inference in large datasets. We clearly define these topics and highlight the context in which the issue can be seen in biomedical data analysis. While we show the relevance of the issues across informatics disciplines, we describe them independently of their domain of application, drawing attention to analytic concerns and presenting a brief summary of relevant research. The issues presented here encompass active areas of research and, as such, a significant set of literature has already been published. Thus, the summaries given here are general. New methods are continually being developed and new challenges will present themselves. Whenever appropriate, we indicate where additional research is needed.

High Dimensionality

High dimensional data are data where each point/sample/element is described by many attributes. For example, a patient can be described by tens of thousands of genes, SNPs or clinical parameters such as x-rays, temperature or culture results. Other examples include data contained in spontaneous reporting systems (SRS), used for pharmacovigilance purposes and Medicare data, which map various medications or vaccines (rows) to possible adverse events (columns). R. Bellman coined the term, “the curse of dimensionality”, in the 1950s to describe the difficulty of optimization in high dimensional sets. High dimensional data are sparse; they show multicollinearity and exhibit model complexity, making model fitting computationally intensive and lending themselves to pitfalls such as model overfitting. For example, classification and clustering algorithms that generally work well in low dimensional situations perform poorly in high dimensions, because of the effect of dimensionality on the distance or similarity measure used by the algorithm. In particular, it is shown in 17 that for certain data distributions the relative difference of the distances of the closest and farthest data points of an independently selected point goes to 0 as the dimension increases. This occurs when all attributes are independent and identically distributed, and it is often said that “in high dimensional spaces, distances between points become relatively uniform”. In this case, the notion of the “nearest neighbor” point is meaningless.

The modeling difficulties introduced by high dimensionality are not insurmountable. We can define a dataset by (1) its size (number of independent entities, such as subjects in a clinical trial) and (2) its dimensionality (number of elements used to describe each subject, such as different clinical parameters measured). We denote the size of a set by n and its dimensionality by p. For example, in the case of microarray data, a cancer sample would count towards n, while the expression measurements for each gene would count towards p, the dimensionality. Then, the following representation of large datasets is useful as it indicates appropriate methodologies for analysis:

  • 1 Large n, small p—Methodologically, this case conforms to the classical statistical paradigm, in which a sufficient number of independent data points provide measurements on a few dimensions. For very large samples, issues such as “statistical” versus “scientific” significance can arise.
  • 2 Small n, large p—This is the paradigm met, for example, in microarray datasets. This case does not conform to the classical statistical paradigm in which n is much larger than p. Techniques employed to compensate for a large p generally fall under the area of feature selection/dimensionality reduction, or are methods specifically developed for this case. Methods include principle components analysis (PCA), compression methods and significance testing to select relevant features.18–22
  • 3 Large n, large p—An example of data that conform to this paradigm is given by the Medicare and Medicaid databases. Depending on the type of research question, the toolkit of the analyst should include both classical statistical methods as well as more modern dimension reduction, classification and clustering methods such as K-nearest neighbors, random forests, CART (classification and regression trees), PCA and many more.

While the above classification is a simplification of what occurs in practice in terms of the type of data collected (image, free text, etc.), it is useful in terms of discussing the underlying principles of data analysis and the appropriate selection of methods. For example, in the “large n, small p” case, depending on the question of interest, appropriate classical statistical methods can be used. These methods provide for the generalizability of the results and aid inference. In the “small n, large p” case, a different set of tools is required. Spurred by the advent of high-throughput technology and data warehousing, these tools are an active area of research in a variety of fields (i.e., statistics, computer science, etc.). One such tool which allows for both inference and generalizability is dimension reduction, or feature selection. Feature selection is the process of selecting a subset of relevant features from high dimensional data in order to build a robust learning model. By removing irrelevant and redundant features, feature selection aids, for example, clustering and classifier performance by: 1) avoiding overfitting and overcoming the curse of dimensionality, 2) enabling the creation of faster models, and 3) providing insight into the underlying processes that generated the data. 23,24 There are three types of feature selection methods: filter methods, wrapper methods and embedded methods. 21,23 Other dimensionality reduction techniques include projection pursuit regression 25 and compression methods.

Less well-known are the blessings associated with high-dimensional data. For example, many “identical” dimensions allow us to “average” for more consistent results, 10,20 allowing the performance of dimension asymptotics that can be used to obtain distributions of functions of interest. Another blessing often encountered within high dimensional structures is the concentration of measure. It involves the tendency of functions to concentrate around their mean, and has been studied by several authors. 10,26 This principle relates to applications in combinatorial optimization, statistical learning, data analysis and data mining. For example, it has been used effectively to derive efficient sampling algorithms for inference in probabilistic graphical models. Many times high dimensional data are generated because the underlying processes measured are continuous in space and/or time. This “approach to continuum” is reflected by approximate finite dimensionality and hence an increasing simplicity of analysis.

Multiple Testing

Multiple testing is the process of subjecting the same dataset to many different statistical tests in the hopes of establishing significance of a hypothesis under study. A typical microarray study, designed to determine discriminant genes between 2 or more groups, requires ~ 20–30,000 simultaneous tests to examine each gene. Here, the type I error rate (false positive risk) is fixed at some reasonable value but the null hypothesis is tested for many attributes. Thus, in a case of n = 10,000 genes and α = 0.05, there are 500 potential type I errors. As the number of tests increases so does the likelihood of observing a significant result due to chance, illustrating the multiple testing problem.

In contrast to single hypothesis testing which is run with the hope that a test is powerful enough to reject a null hypothesis, large-scale testing is often used to identify a subset of “interesting” cases that deserve further investigation. Therefore, standard methods such as the family-wise error rate (FWER) and even the more commonly used Benjamini-Hochberg false discovery rate (FDR) are often too stringent. The FDR is the expected proportion of erroneous rejections among all null hypothesis rejections and it is equivalent to the FWER when all hypotheses are true, but it is smaller otherwise, which makes the practical difference between them neither trivial nor small. 27 A variant of the expected proportion of falsely identified significant items, known as the local false discovery rate, is proposed in Efron 2004 28 for use in large-scale hypothesis testing. When concurrent tests on a given dataset are ordered by significance (p-value), multiple testing procedures simply limit the number of tests that are identified as significant. This can be helpful when considering scientific significance over statistical significance. While new FDR methods are being developed, popular methods include Benjamini-Hochberg, 27 empiric Bayes approaches 28–30 and others. 31,32 The selection of an FDR method should be based on knowledge about the underlying data structure such as distribution and dependence structure.

Statistical Significance versus Scientific Significance

When the number of points, for example the number of subjects in a study, is really large, it is possible, for a given hypothesis under study, to observe statistical significance even though the hypothesis may not be scientifically plausible. For example, when studying associations in a large dataset using simple methods such as χ2 statistics, it is possible to obtain statistically significant results that do not have scientific meaning. In a preliminary analysis, Cao, et al 33 found the pair (hypertension, suicide) to be statistically significant via standard methods. This is clearly not clinically plausible and prompted Cao et al to develop a method for the calibration of the critical value of the χ2 statistic to help the identification of an appropriate critical point beyond which significance can be declared. An alternative is to transform the testing problem into an estimation problem, by constructing, for example, appropriate confidence intervals. Another option is the use of biological enrichment, which enriches statistical results with domain information. For example, Gene Ontology (GO) enrichment is used to validate lists of statistically significant genes found by differential analysis with biological information encoded in the GO. It assesses the functional similarity of genes in the provided list with respect to the biological processes they comprise.

Dependence

Very large datasets are unlikely to arise in an independent, identically distributed manner. For example, although large clinical databases contain information on different patients, and these subjects are independent, they also contain measurements on the same patient over time and these measurements are dependent. Examples include daily glucose measurements or white blood cell count data taken over a specified period on individuals undergoing long-term dialysis for chronic renal failure. Measurements close in time tend to be correlated with one another. To obtain valid inferences for time-dependent data, a variety of methods have been developed in time series, longitudinal and functional data analysis areas of biostatistics.

Even information on different patients may exhibit correlation. For example, patients treated by the same clinical team are more likely to have similar outcomes. Because of this lack of independence, standard statistical methods used for sample estimation and analysis will underestimate values such as the required sample size. This is typically a factor in computer-based clinical decision support system studies. Chuang, et al 34 surveyed 24 such studies and found that none took into account this type of patient clustering in sample size calculations and only 14 (58%) took this factor into account at all. One solution is to multiply standard sample size estimates by a design effect term based on an intracluster correlation measurement. Another option is to use sample size formulas appropriate for correlated data. 35

High dimensional sets, especially, are subject to the existence of nontrivial, highly correlated data points or subspaces. 36 In the case of gene expression data, it is a reasonable assumption that genes or proteins that act together will exhibit strong correlation. For example, transcription factors can regulate key genes in multiple signal transduction pathways, creating a set of correlated factors. However, global correlation is also an important factor. Recent literature has indicated that underlying dependence structures in microarray data, as measured by pairwise gene expression correlation, show an average of correlation over 0.84, 37 suggesting that dependence between genes is a factor that we must consider in biological data analysis.

Specifically, dependent samples and/or dimensions will not reduce the variability of the data and thus will not improve analysis. This affects statistical modeling and the performance of the methods that assume independence, so methods that account for dependence need to be used. The study of dependence is an important and active area of research. Multivariate analysis methods to improve analysis of high-throughput and correlated genetic data have been proposed but are not widely known or used. 38,39 Similarly, multiple testing procedures, such as Benjamini-Hochberg, are rooted in the assumption that the variables are independent, and FDR methods that do not account for this could produce unreliable results. Methods that deal with this problem continue to appear in the literature. 40–42 Adjustments to existing FDR methods that can accommodate specific types of dependence structures have been proposed. 41,43–46 However, even these adjustments tend to be conservative. Again, method selection should be based on knowledge about the underlying dependence structure of the data.

Another consideration is the effect of data transformations on the dependence structure of the data. A typical goal in microarray studies is to use correlation information to reconstruct or reverse-engineer molecular pathways and networks. However, data transformations such as normalization methods have the potential to destroy or even create spurious correlation information, rendering flawed inferred networks. The practice of data transformation is not limited to the microarray analysis arena; the scaling of variables for clustering is a well-known headache. The most commonly used idea among practitioners is to standardize or autoscale individual variables. However, this is only effective in equalizing values if the variables themselves are independent. 1,47 In fact, the effect of transformation has not been well-studied and has only become a subject of research in the last 5 years. 48,49

Information Measurement

“Information” is a concept that spans many scientific fields including communication theory, biology, economics, law, and statistics. In its semantic context, the term information is used in an intuitive sense, but in its technical context, information is a well-defined function that quantifies the extent of uncertainty differentials. Large datasets provide a tremendous volume of data, but not necessarily a tremendous volume of information—the size of a dataset is not a guarantee that the data will contain information about the question of interest.

Large datasets are usually complex in structure and challenging in extracting meaningful information from them. One way of extracting information is through measures of computational and algorithmic complexity; another is through quantifying variability in these sets. Information measures can be used to guide decisions associated with the selection of appropriate algorithms for processing and extracting information, such that, for example, given a dataset with known characteristics, one can select an optimal classifier. However, it should be kept in mind that the choice of a particular algorithm biases the analysis towards solutions that play to the algorithm's strengths. The very practical problem of selecting a classification or clustering algorithm is not well addressed in the literature. 47

There are two types of information measures met in the literature, those that use probabilities and are thus stochastic information measures, and deterministic information measures. Examples of stochastic information measures include Fisher's information, Shannon's information, Kullback–Leibler information, and mutual information. Deterministic measures include various information functions and the algorithmic information content (AIC) measure. [triangle] discusses each of these in more detail. 50–54 These information measures can be used to determine relationships between variables, similar to correlation metrics, and are thus useful in any kind of association study, or to quantify variability of features.

Table 2
Table 2 A List of Important Information Metrics

The choice of information and complexity measure (stochastic or deterministic) must be closely aligned with the task performed. For instance, Sohn 8 derived a set of relevant data characteristics and used regression analysis to develop a statistical metamodel that compares the classification performances of several algorithms. Relevant data complexity measures that can be used for assessing computational complexity are discussed further in Sotoca, et al. 55

Information Management

Information management is necessary to ensure that relevant and accurate information critical for analysis is identified. To that end, we note data quality management, integration, access control/privacy, and performance as information management issues relevant to the analysis of large datasets.

Data quality problems include missing data points, outliers, data glitches, unreported changes in scale, format, or measurement, and many others. Too many missing or erroneous values can give an inaccurate view of the data and corrupt further data analysis. Because repeat experimentation is often expensive, a variety of methods have been developed to account for such data. Some of these issues can be addressed by using appropriate statistical methods, 56,57 while others require the implementation of specialized techniques for their identification, correction, and management. 58,59

Data integration is required to provide seamless access to diverse and voluminous data sources while maintaining and improving the integrity of data to elucidate normal and disease physiology; it is a valuable step in improving data analysis. 60,61 While the general area of integration presents many challenges, here we focus on analysis issues resulting from such integration. For example, because many microarray datasets are small and high-dimensional, dataset integration is often desirable as a leverage to increase sample size. However, this is complicated by systemic issues such as differences in technology, protocols, and experimental conditions across datasets. Systemic variability can overwhelm biological variability, creating a batch effect which confounds analysis. Literature is divided on the severity of systemic variability, 62 but experiment integration is an active area of research 63 with methods falling into two main categories: statistical meta-analysis 64–67 and heterogeneous data integration systems. 68–71

Conclusions

As shown by the exponential growth of key databases in this arena, large datasets are a growing part of regular practice in biomedicine. In the healthcare setting, thoughtful analysis can optimize the quality and cost of care. Similarly, genomic medicine provides sequence, transcriptomic, proteomic, and other information that can be further analyzed to tie developments in biology to the practice of medicine. To better understand the datasets we deal with, we have characterized analytic goals and presented a detailed discussion of germane issues for large datasets with a focus on appropriate methodologies available to address these concerns and areas of continued research. This lends itself to better study design, a structured analysis of data, as well as improved generalizability and inference. A firm understanding of the challenges and statistical technology involved ultimately contributes to better science.

Here, we further suggest that this motivates a focused effort by the community to address these issues in the forms of best practices guidelines, interdisciplinary panels, invited papers, curriculum enhancement and improved reporting practices. The large gap between “typical” and “best” practices for the analysis of large datasets can be narrowed. Available resources should match best practices, and/or researchers should have the tools to access or develop more appropriate platforms. Transparent reporting indicating how fundamental issues are addressed will increase trust in the reproducibility of the results. Thus, it is perhaps appropriate to consider the creation of guidelines not only for analysis, but also for the reporting of the analyses used. Guidance on this topic can be provided through expert panel formation and relevant publications such as Lang and Secic (2007). 72 However, we note that existing literature on the topic of reporting in medicine does not cover the specific issues found in the analysis of large datasets.

We believe that it is fundamentally important for researchers to have a basic understanding of the unique issues encountered in large dataset analysis to aid generalizability, inference, and reporting of generated results. These proposed forums serve the purpose of facilitating discussion on challenging issues and the feasibility for establishing firm guidelines in the art of analysis.

Acknowledgments

The authors thank Dr. Andrew Talal for his valuable contributions and insights in reviewing this paper.

Footnotes

Dr. Markatou's research was funded by NSF DMS-0504957 and OBE/CBER/FDA. Dr. Hripcsak is supported by NLM R01 LM06910 “Discovering and applying knowledge in clinical databases”. Anshu Sinha is supported by the NLM Informatics Research Training Program (T15 LM007079-17).

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