Jouni K. Seppänen

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

No clear patterns in molecular changes underlying the malignant processes in lung cancer of different histological types have been found so far. To identify critical genes in lung cancer progression we compared the expression profile of cancer related genes in 14 pulmonary adenocarcinoma patients with normal lung tissue by using the cDNA array technique. Principal component analyses (PCA) and permutation test were used to detect the differentially expressed genes. The expression profiles of 10 genes were confirmed by semi-quantitative real-time RT–PCR. In tumour samples, as compared to normal lung tissue, the up-regulated genes included such known tumour markers as CCNB1, PLK, tenascin, KRT8, KRT19 and TOP2A. The down-regulated genes included caveolin 1 and 2, and TIMP3. We also describe, for the first time, down-regulation of the interesting SOCS2 and 3, DOC2 and gravin. We show that silencing of SOCS2 is not caused by methylation of exon 1 of the gene. In conclusion, by using the cDNA array technique we were able to reveal marked differences in the gene expression level between normal lung and tumour tissue and find possible new tumour markers for pulmonary adenocarcinoma.

Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer

The expression patterns of cancer-related genes in 13 cases of squamous cell lung cancer (SCC) were characterized and compared with those in normal lung tissue and 13 adenocarcinomas (AC), the other major type of nonsmall cell lung cancer (NSCLC). cDNA array was used to screen the gene expression levels and the array results were verified using a real-time reverse-transcriptase-polymerase chain reaction (RT-PCR). Thirty-nine percent of the 25 most upregulated and the 25 most downregulated genes were common to SCC and AC. Of these genes, DSP, HMGA1 (alias HMGIY), TIMP1, MIF, CCNB1, TN, MMP11, and MMP12 were upregulated and COPEB (alias CPBP), TYROBP, BENE, BMPR2, SOCS3, TIMP3, CAV1, and CAV2 were downregulated. The expression levels of several genes from distinct protein families (cytokeratins and hemidesmosomal proteins) were markedly increased in SCC compared with AC and normal lung. In addition, several genes, overexpressed in SCC, such as HMGA1, CDK4, IGFBP3, MMP9, MMP11, MMP12, and MMP14, fell into distinct chromosomal loci, which we have detected as gained regions on the basis of comparative genomic hybridization data. Our study revealed new candidate genes involved in NSCLC.

Dense itemsets

Frequent itemset mining has been the subject of a lot of work in data mining research ever since association rules were introduced. In this paper we address a problem with frequent itemsets: that they only count rows where all their attributes are present, and do not allow for any noise. We show that generalizing the concept of frequency while preserving the performance of mining algorithms is nontrivial, and introduce a generalization of frequent itemsets, dense itemsets. Dense itemsets do not require all attributes to be present at the same time; instead, the itemset needs to define a sufficiently large submatrix that exceeds a given density threshold of attributes present.We consider the problem of computing all dense itemsets in a database. We give a levelwise algorithm for this problem, and also study the top-

Geometric and combinatorial tiles in 0-1 data

k

Caveolins as tumour markers in lung cancer detected by combined use of cDNA and tissue microarrays

variations, i.e., finding the k densest sets with a given support, or the k best-supported sets with a given density. These algorithms select the other parameter automatically, which simplifies mining dense itemsets in an explorative way. We show that the concept captures natural facets of data sets, and give extensive empirical results on the performance of the algorithms. Combining the concept of dense itemsets with set cover ideas, we also show that dense itemsets can be used to obtain succinct descriptions of large datasets. We also discuss some variations of dense itemsets.

Finding low-entropy sets and trees from binary data

In this paper we introduce a simple probabilistic model, hierarchical tiles, for 0-1 data. A basic tile (X,Y,p) specifies a subset X of the rows and a subset Y of the columns of the data, i.e., a rectangle, and gives a probability p for the occurrence of 1s in the cells of X × Y. A hierarchical tile has additionally a set of exception tiles that specify the probabilities for subrectangles of the original rectangle. If the rows and columns are ordered and X and Y consist of consecutive elements in those orderings, then the tile is geometric; otherwise it is combinatorial. We give a simple randomized algorithm for finding good geometric tiles. Our main result shows that using spectral ordering techniques one can find good orderings that turn combinatorial tiles into geometric tiles. We give empirical results on the performance of the methods.

Early Environment and Neurobehavioral Development Predict Adult Temperament Clusters

To identify new potential diagnostic markers for lung cancer, the expression profiles of 37 lung tumours were analysed using cDNA arrays. Seven samples were from small‐cell lung cancer (SCLC), two from large‐cell neuroendocrine tumours (LCNEC), and 28 from other non‐small‐cell lung cancers (mainly squamous cell cancer and adenocarcinoma). Principal component analysis and the permutation test were used to detect differences in the gene expression profiles and a set of genes was found that distinguished high‐grade neuroendocrine carcinomas (SCLC and LCNEC) from other lung cancers. In addition, several genes, such as caveolin‐1 (CAV1) and caveolin‐2 (CAV2), were constantly deregulated in all types of tumour sample, compared with normal tissue. The expression of these two genes was investigated further at the protein level on a tissue microarray containing tumours from 161 patients and normal tissues. Immunostaining for CAV1 was negative in 48% of tumours, whereas 28% of the tumours did not express CAV2. Lack of CAV1 protein expression was not caused by methylation or mutation. In stage I adenocarcinomas, CAV2 protein expression correlated with shorter survival. In conclusion, the present study was able to identify genes that have not previously been implicated in lung cancer by the combined use of two different array techniques. Some of these genes may provide novel diagnostic markers for lung cancer. Copyright

A Simple Algorithm for Topic Identification in 0–1 Data

The discovery of subsets with special properties from binary data hasbeen one of the key themes in pattern discovery. Pattern classes suchas frequent itemsets stress the co-occurrence of the value 1 in the data. While this choice makes sense in the context of sparse binary data, it disregards potentially interesting subsets of attributes that have some other type of dependency structure. We consider the problem of finding all subsets of attributes that have low complexity. The complexity is measured by either the entropy of the projection of the data on the subset, or the entropy of the data for the subset when modeled using a Bayesian tree, with downward or upward pointing edges. We show that the entropy measure on sets has a monotonicity property, and thus a levelwise approach can find all low-entropy itemsets. We also show that the tree-based measures are bounded above by the entropy of the corresponding itemset, allowing similar algorithms to be used for finding low-entropy trees. We describe algorithms for finding all subsets satisfying an entropy condition. We give an extensive empirical evaluation of the performance of the methods both on synthetic and on real data. We also discuss the search for high-entropy subsets and the computation of the Vapnik-Chervonenkis dimension of the data.

Model-Independent Bounding of the Supports of Boolean Formulae in Binary Data

Background Investigation of the environmental influences on human behavioral phenotypes is important for our understanding of the causation of psychiatric disorders. However, there are complexities associated with the assessment of environmental influences on behavior. Methods/Principal Findings We conducted a series of analyses using a prospective, longitudinal study of a nationally representative birth cohort from Finland (the Northern Finland 1966 Birth Cohort). Participants included a total of 3,761 male and female cohort members who were living in Finland at the age of 16 years and who had complete temperament scores. Our initial analyses (Wessman et al., in press) provide evidence in support of four stable and robust temperament clusters. Using these temperament clusters, as well as independent temperament dimensions for comparison, we conducted a data-driven analysis to assess the influence of a broad set of life course measures, assessed pre-natally, in infancy, and during adolescence, on adult temperament. Results Measures of early environment, neurobehavioral development, and adolescent behavior significantly predict adult temperament, classified by both cluster membership and temperament dimensions. Specifically, our results suggest that a relatively consistent set of life course measures are associated with adult temperament profiles, including maternal education, characteristics of the family’s location and residence, adolescent academic performance, and adolescent smoking. Conclusions Our finding that a consistent set of life course measures predict temperament clusters indicate that these clusters represent distinct developmental temperament trajectories and that information about a subset of life course measures has implications for adult health outcomes.

Temperament Clusters in a Normal Population: Implications for Health and Disease

Topics in 0–1 datasets are sets of variables whose occurrences are positively connected together. Earlier, we described a simple generative topic model. In this paper we show that, given data produced by this model, the lift statistics of attributes can be described in matrix form. We use this result to obtain a simple algorithm for finding topics in 0–1 data. We also show that a problem related to the identification of topics is NP-hard. We give experimental results on the topic identification problem, both on generated and real data.