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The properties of high-dimensional data spaces: implications for exploring gene and protein expression data

Key Points

  • The application of several high-throughput genomic and proteomic technologies to address questions in cancer diagnosis, prognosis and prediction generate high-dimensional data sets.

  • The multimodality of high-dimensional cancer data, for example, as a consequence of the heterogeneous and dynamic nature of cancer tissues, the concurrent expression of multiple biological processes and the diverse and often tissue-specific activities of single genes, can confound both simple mechanistic interpretations of cancer biology and the generation of complete or accurate gene signal transduction pathways or networks.

  • The mathematical and statistical properties of high-dimensional data spaces are often poorly understood or inadequately considered. This can be particularly challenging for the common scenario where the number of data points obtained for each specimen greatly exceed the number of specimens.

  • Data are rarely randomly distributed in high-dimensions and are highly correlated, often with spurious correlations.

  • The distances between a data point and its nearest and farthest neighbours can become equidistant in high dimensions, potentially compromising the accuracy of some distance-based analysis tools.

  • Owing to the 'curse of dimensionality' phenomenon and its negative impact on generalization performance, for example, estimation instability, model overfitting and local convergence, the large estimation error from complex statistical models can easily compromise the prediction advantage provided by their greater representation power. Conversely, simpler statistical models may produce more reproducible predictions but their predictions may not always be adequate.

  • Some machine learning methods address the 'curse of dimensionality' in high-dimensional data analysis through feature selection and dimensionality reduction, leading to better data visualization and improved classification.

  • It is important to ensure that the generalization capability of classifiers derived by supervised learning methods from high-dimensional data before using them for cancer diagnosis, prognosis or prediction. Although this can be assessed initially through cross-validation methods, a more rigorous approach is needed, that is, to validate classifier performance using a blind validation data set(s) that was not used during supervised learning.


High-throughput genomic and proteomic technologies are widely used in cancer research to build better predictive models of diagnosis, prognosis and therapy, to identify and characterize key signalling networks and to find new targets for drug development. These technologies present investigators with the task of extracting meaningful statistical and biological information from high-dimensional data spaces, wherein each sample is defined by hundreds or thousands of measurements, usually concurrently obtained. The properties of high dimensionality are often poorly understood or overlooked in data modelling and analysis. From the perspective of translational science, this Review discusses the properties of high-dimensional data spaces that arise in genomic and proteomic studies and the challenges they can pose for data analysis and interpretation.

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Figure 1: Cluster separability in data space.
Figure 2: High dimensional expression data are multimodal.
Figure 3: Model fitting, dimensionality and the blessings of smoothness.
Figure 4: The curse of dimensionality and the bias or variance dilemma.
Figure 5: Dimensionality reduction.


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We wish to thank D. J. Miller (Department of Electrical Engineering, The Pennsylvania State University) for critical reading of the manuscript. Some of the issues we discuss may appear overly simplified to experts. Several of the emerging concepts have yet to appear in the biomedical literature and publications might not be accessible through PubMed (but are often found at an author's or journal's homepage or at CiteSeer). Many of the engineering and computer science works published in 'proceedings' represent peer-reviewed publications. This work was supported in part by Public Health Service grants R01-CA096483, U54-CA100970, R33-EB000830, R33-CA109872, 1P30-CA51008, R03-CA119313, and a U.S. Department of Defense Breast Cancer Research Program award BC030280.

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Correspondence to Robert Clarke.

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Gene Ontology

Kyoto Encyclopedia of Genes and Genomes

Protein Information Resource




A significance test for assessing hypotheses about population means, usually a test of the equality of means of two independent populations.

False discovery rate

A univariate statistical method that controls the type I (false-positive) errors to correct for multiple testing.


A cluster consists of a relatively high density of data points separated from other clusters by a relative low density of points; patterns within a cluster are more similar to each other than patterns belonging to different clusters.

Massively parallel

A large number of simultaneous processes; in biology, a living cell has multiple, concurrently active processes that are reflected in the proteome and its underlying transcriptome.

Trap of self-fulfilling prophesy

With thousands of measurements and the concurrent presence of multiple sub-phenotypes, intuitively logical but functionally incorrect associations may be implied between a signal's (gene or protein) perceived or known function in a biological system or phenotype of interest.

Euclidean space

Any mathematical space that is a generalization of the two- and three-dimensional spaces described by the axioms and definitions of Euclidean geometry, for example, properties of angles of plane triangles and of straight and parallel lines.

k-Means clustering algorithm

A method of cluster analysis in which, from an initial partition of the observations into k clusters, each observation in turn is examined and reassigned, if appropriate, to a different cluster, in an attempt to optimize a predefined numerical criterion that measures, in some sense, the quality of the cluster solution.


A coordinate-based data structure in which the information is represented by a magnitude and a direction.

Hard clustering

Any clustering method that forces a data point to belong only to a single cluster.

Test pattern

Also known as the testing set, this is a data point(s) that was not part of the training set, for example, in a leave-one-out approach the testing set is the sample that was left out during training.

Training set

The sample of observations from which a classification function is derived.

Null hypothesis

The hypothesis that there is no difference between the two groups for a variable that is being compared.

Family-wise error rate

The probability of making any error in a given family of inferences, rather than a per-comparison error rate or a per-experiment error rate.

Clustering algorithm

Procedure designed to find natural groupings or clusters in multidimensional data on the basis of measured or perceived similarities among the patterns.


A measure that substitutes for (and correlates with) a real endpoint but has no assured relationship; for example, tumour shrinkage in response to chemotherapy (surrogate) does not assure that the patient will live longer (endpoint).

Soft clustering

Any clustering method that allows a data point to be a member of more than one cluster.

Vector space

Space where data are represented by vectors that may be scaled and added as in linear algebra; two-dimensional Euclidean space is one form of vector space.

Metric space

A data space where the distance between each data point is specifically defined.

Hierarchical clustering

A series of models for a set of observations, where each model results from adding (or deleting) parameters from other models in the series.

Logistic regression

A method of analysis concerned with estimating the parameters in a postulated relationship between a response variable (binary for logistic regression) and one or more explanatory variables.


A higher-dimensional generalization of the concepts of a plane in three-dimensional (or a line in two-dimensional) Euclidean geometry. A plane is a surface where, for any two points on the surface, the straight line that passes through those points also lies on the surface.

Kernel function

A mathematical transform operated upon one or multiple input variables; inner product or convolution is a popular form of kernel function.

Regression coefficient

A component of a statistical model in which a response variable is estimated by a number of explanatory variables, each combined with a regression coefficient that gives the estimated change in the response variable corresponding to a unit change in the appropriate explanatory variable.

Agglomerative hierarchical clustering

Methods of cluster analysis that begin with each individual in a separate cluster and then, in a series of steps, combine individuals, and later clusters, into new and larger clusters, until a final stage is reached where all individuals are members of a single group.

Missing value estimation

When an expected value is not reported for a specific gene or protein the missing value can be estimated and the estimated value used for data analysis.

Normally distributed

The value of a random variable(s) follows a probability-density function completely specified by the mean and variance.

Parametric statistical model

A statistical model, the probability distribution of which is specified by a relatively small set of quantitative parameters.

Subcubical neighbourhood

A smaller cubical area of a larger hypercubical space.

Hypercubical neighbourhood

A higher-dimensional generalization of the concepts of a cubic neighbourhood in three-dimensional Euclidean geometry.

Bootstrap re-sampling

A statistical method that iteratively uses subsets of the original data set to estimate the bias and variance for a classification algorithm.

Scale-free behaviour

The behaviour of an estimator is scale-free if it depends only on the ranks of the observations, for example, the estimator is equally accurate whether the logarithms of the observations or the values of the observations are used for analysis.

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Clarke, R., Ressom, H., Wang, A. et al. The properties of high-dimensional data spaces: implications for exploring gene and protein expression data. Nat Rev Cancer 8, 37–49 (2008).

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