CS 5984: Application of Basic Clustering Algorithms to Find Expression Modules in Cancer

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CS 5984: Application of Basic Clustering Algorithms to Find Expression Modules in Cancer T. M. Murali January 31, 2006

Innovative Application of Hierarchical Clustering A module map showing conditional activity of expression modules in cancer, Eran Segal, Nir Friedman, Daphne Koller and Aviv Regev, Nature Genetics 36, 1090 1098, 2004 Analyse gene expression data to find groups of genes expressed in concert between different cancers. Use hierarchical clustering innovatively.

Key Ideas Group genes into predefined gene sets, e.g., groups of genes with the same functional annotation. Convert gene-by-array matrix into gene-set-by-array matrix. Hierarchically cluster gene sets in this matrix. Identify interesting gene set clusters (nodes) in the tree. In each gene set cluster, remove genes not expressed consistently with the cluster.

Gene Expression Data Sets

Data Normalisation

Data Normalisation Needed because some arrays measure absolute value of gene expression and others measure relative values. Affymetrix microarrays: take logarithm to the base-2 and zero transform within data set. cdna microarrays:

Data Normalisation Needed because some arrays measure absolute value of gene expression and others measure relative values. Affymetrix microarrays: take logarithm to the base-2 and zero transform within data set. cdna microarrays: zero transform within data set.

Pre-defined Genes Sets

Computing Gene-Set-By-Array Matrix Goal is to construct a gene-set-by-array matrix. For each gene set-array pair, find an average expression value of that gene set in that array.

Computing Gene-Set-By-Array Matrix Goal is to construct a gene-set-by-array matrix. For each gene set-array pair, find an average expression value of that gene set in that array. A gene is induced (respectively, repressed in an array if its change in expression is 2 (respectively, 2). For each gene set-array pair, compute the fraction of genes induced or repressed. Use these values in the gene-set-by-array matrix.

Computing Significant Entries in the Gene-Set-By-Array Matrix Many entries in the gene-set-by-array matrix may not be statistically significant.

Computing Significant Entries in the Gene-Set-By-Array Matrix Many entries in the gene-set-by-array matrix may not be statistically significant. For a given array, fraction of induced genes in a gene set may be close to the fraction of induced genes in the array.

Computing Significant Entries in the Gene-Set-By-Array Matrix Many entries in the gene-set-by-array matrix may not be statistically significant. For a given array, fraction of induced genes in a gene set may be close to the fraction of induced genes in the array. Statistical test: for a given array, is the fraction of induced genes in a gene set much larger than the fraction of induced genes in the entire array?

Computing Significant Entries in the Gene-Set-By-Array Matrix Many entries in the gene-set-by-array matrix may not be statistically significant. For a given array, fraction of induced genes in a gene set may be close to the fraction of induced genes in the array. Statistical test: for a given array, is the fraction of induced genes in a gene set much larger than the fraction of induced genes in the entire array? Compute the p-value of the fraction using the hypergeometric test. Do so for every gene-set-array pair. Use false discovery rate correction to account for multiple hypotheses testing. Replace insignificant entries by 0.

Computing the Significance of an Entry in the Gene-Set-By-Array Matrix Let m be the number of genes in the data set. let m G be the number of genes in a gene set G. Let u a be the number of induced genes in an array a. let u G,a be the number of genes in G induced in a.

Computing the Significance of an Entry in the Gene-Set-By-Array Matrix Let m be the number of genes in the data set. let m G be the number of genes in a gene set G. Let u a be the number of induced genes in an array a. let u G,a be the number of genes in G induced in a. Informally, u G,a /m G u a /m is not statistically significant.

Computing the Significance of an Entry in the Gene-Set-By-Array Matrix Let m be the number of genes in the data set. let m G be the number of genes in a gene set G. Let u a be the number of induced genes in an array a. let u G,a be the number of genes in G induced in a. Informally, u G,a /m G u a /m is not statistically significant. Formally, what is the probability that if we pick m G genes at random from m genes, we will select u G,a or more that are induced in a?

Computing the Significance of an Entry in the Gene-Set-By-Array Matrix Let m be the number of genes in the data set. let m G be the number of genes in a gene set G. Let u a be the number of induced genes in an array a. let u G,a be the number of genes in G induced in a. Informally, u G,a /m G u a /m is not statistically significant. Formally, what is the probability that if we pick m G genes at random from m genes, we will select u G,a or more that are induced in a? i u G,a

Computing the Significance of an Entry in the Gene-Set-By-Array Matrix Let m be the number of genes in the data set. let m G be the number of genes in a gene set G. Let u a be the number of induced genes in an array a. let u G,a be the number of genes in G induced in a. Informally, u G,a /m G u a /m is not statistically significant. Formally, what is the probability that if we pick m G genes at random from m genes, we will select u G,a or more that are induced in a? i u G,a ( ua )( m ua i m G i ( m m G ) )

If this probability is at most a user-specified threshold, we deem that entry to be statistically significant. Computing the Significance of an Entry in the Gene-Set-By-Array Matrix Let m be the number of genes in the data set. let m G be the number of genes in a gene set G. Let u a be the number of induced genes in an array a. let u G,a be the number of genes in G induced in a. Informally, u G,a /m G u a /m is not statistically significant. Formally, what is the probability that if we pick m G genes at random from m genes, we will select u G,a or more that are induced in a? i u G,a ( ua )( m ua i m G i ( m m G ) )

Hierarchical Clustering Start from a gene-set-by-array matrix containing fraction of induced/repressed genes. Fraction is negative if repressed. Apply bottom-up hierarchical clustering. Vector at internal node is

Hierarchical Clustering Start from a gene-set-by-array matrix containing fraction of induced/repressed genes. Fraction is negative if repressed. Apply bottom-up hierarchical clustering. Vector at internal node is average of vectors at descendant leaves.

Hierarchical Clustering Start from a gene-set-by-array matrix containing fraction of induced/repressed genes. Fraction is negative if repressed. Apply bottom-up hierarchical clustering. Vector at internal node is average of vectors at descendant leaves. Which nodes do we select as clusters in the tree?

Hierarchical Clustering Start from a gene-set-by-array matrix containing fraction of induced/repressed genes. Fraction is negative if repressed. Apply bottom-up hierarchical clustering. Vector at internal node is average of vectors at descendant leaves. Which nodes do we select as clusters in the tree? Associate each interior node with Pearson correlation between the two children. Cluster node whose Pearson correlation differs by more than 0.05 from the Pearson correlation of its parent.

Turning Clusters into Modules Each cluster is the union of descendant gene sets (leaves). Module Cluster minus genes whose expression is not consistent with the rest of the cluster.

Testing Consistency of a Gene with a Gene Set Let g be the gene and G be the gene set G.

Testing Consistency of a Gene with a Gene Set Let g be the gene and G be the gene set G. Let I (respectively, R) be the set of arrays in which G is significantly induced (respectively, repressed). For an array a in I (or R), let p a be the fraction of genes that are induced (or repressed) by two-fold or more in a.

Testing Consistency of a Gene with a Gene Set Let g be the gene and G be the gene set G. Let I (respectively, R) be the set of arrays in which G is significantly induced (respectively, repressed). For an array a in I (or R), let p a be the fraction of genes that are induced (or repressed) by two-fold or more in a. Measure extent to which g s expression changed by more (or less) than two-fold in the arrays in I (or R):

Testing Consistency of a Gene with a Gene Set Let g be the gene and G be the gene set G. Let I (respectively, R) be the set of arrays in which G is significantly induced (respectively, repressed). For an array a in I (or R), let p a be the fraction of genes that are induced (or repressed) by two-fold or more in a. Measure extent to which g s expression changed by more (or less) than two-fold in the arrays in I (or R): Score(g) = log(p a )+ log(p a ) a I g is induced in a a R g is repressed in a

Testing Consistency of a Gene with a Gene Set Let g be the gene and G be the gene set G. Let I (respectively, R) be the set of arrays in which G is significantly induced (respectively, repressed). For an array a in I (or R), let p a be the fraction of genes that are induced (or repressed) by two-fold or more in a. Measure extent to which g s expression changed by more (or less) than two-fold in the arrays in I (or R): Score(g) = log(p a )+ log(p a ) a I g is induced in a a R g is repressed in a No contribution from an array in I (or R) is g is not induced (or not repressed) in a. Larger contribution from arrays with fewer induced genes. Compute statistical significance of this score.

Computing Statistical Significance of Score(g) Score(g) = log(p a ) + log(p a ) a I g is induced in a a R g is repressed in a

Computing Statistical Significance of Score(g) Score(g) = a I g is induced in a log(p a ) + a R g is repressed in a log(p a ) Null hypotheses: genes in each array are randomly permuted, i.e., the p a induced genes in an array a I are chosen randomly.

Computing Statistical Significance of Score(g) Score(g) = a I g is induced in a log(p a ) + a R g is repressed in a log(p a ) Null hypotheses: genes in each array are randomly permuted, i.e., the p a induced genes in an array a I are chosen randomly. Each element in Score(g) is an independent binary random variable. Random variable takes the value log(p a ) with probability p a and the value 0 with the probability 1 p a.

Computing Statistical Significance of Score(g) Score(g) = a I g is induced in a log(p a ) + a R g is repressed in a log(p a ) Null hypotheses: genes in each array are randomly permuted, i.e., the p a induced genes in an array a I are chosen randomly. Each element in Score(g) is an independent binary random variable. Random variable takes the value log(p a ) with probability p a and the value 0 with the probability 1 p a. Mean of Score(g) is a I R p a log p a and variance is a I R p a(1 p a ) log 2 p a.

Computing Statistical Significance of Score(g) Score(g) = a I g is induced in a log(p a ) + a R g is repressed in a log(p a ) Null hypotheses: genes in each array are randomly permuted, i.e., the p a induced genes in an array a I are chosen randomly. Each element in Score(g) is an independent binary random variable. Random variable takes the value log(p a ) with probability p a and the value 0 with the probability 1 p a. Mean of Score(g) is a I R p a log p a and variance is a I R p a(1 p a ) log 2 p a. Central limit theorem that the distribution of Score(g) is well-approximated by a Gaussian distribution with this mean and variance. Assess statistical significance by computing the tail of this Gaussian.

Further Analysis Statistical significance of computed modules using leave-one-out cross validation (read supplement). Compute enrichment of clinical annotations of the arrays in a module. Visualisation of modules. Literature-based analysis of modules

Conclusions Used pre-defined gene sets to drive hierarchical clustering algorithm. Remove genes from a cluster of gene sets if the gene s expression profile deviates from the cluster. Automatically decide which arrays are part of a module. Natural segue into lectures on biclustering where we will automatically decide which arrays and which genes to include in a bicluster.

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