Biomedical subjects

Tero Aittokallio

Publications and source records attributed to Tero Aittokallio.

At least 19 recordsLinked to original sources

PubMed2006

Automated pattern ranking in differential display data analysis.

Gene expression analysis by differential display (DD) is limited by the labor-intensive visual evaluation of the electrophoretic data traces. We describe a flexible method for computer-assisted ranking of expression patterns in data from DD experiments. The method is based on a pairwise alignment and comparison of the quantitative trace data with respect to specific expression patterns defined by the investigator. The observed patterns are ranked according to a score value that identifies the most potential findings to be confirmed visually instead of the vast amount of original results. This two-step approach, enabled by the efficient computer algorithm for gene expression pattern comparison, will increase the percentage of true-positive findings chosen for the tedious downstream processing, while minimizing the cost and labor involved in large scale DD data analysis.

Algorithms↗

PubMed2005

Improving missing value estimation in microarray data with gene ontology.

MOTIVATION: Gene expression microarray experiments produce datasets with frequent missing expression values. Accurate estimation of missing values is an important prerequisite for efficient data analysis as many statistical and machine learning techniques either require a complete dataset or their results are significantly dependent on the quality of such estimates. A limitation of the existing estimation methods for microarray data is that they use no external information but the estimation is based solely on the expression data. We hypothesized that utilizing a priori information on functional similarities available from public databases facilitates the missing value estimation. RESULTS: We investigated whether semantic similarity originating from gene ontology (GO) annotations could improve the selection of relevant genes for missing value estimation. The relative contribution of each information source was automatically estimated from the data using an adaptive weight selection procedure. Our experimental results in yeast cDNA microarray datasets indicated that by considering GO information in the k-nearest neighbor algorithm we can enhance its performance considerably, especially when the number of experimental conditions is small and the percentage of missing values is high. The increase of performance was less evident with a more sophisticated estimation method. We conclude that even a small proportion of annotated genes can provide improvements in data quality significant for the eventual interpretation of the microarray experiments. AVAILABILITY: Java and Matlab codes are available on request from the authors. SUPPLEMENTARY MATERIAL: Available online at http://users.utu.fi/jotatu/GOImpute.html.

Algorithms↗

PubMed2005

Integrating probe-level expression changes across generations of Affymetrix arrays.

There is an urgent need for bioinformatic methods that allow integrative analysis of multiple microarray data sets. While previous studies have mainly concentrated on reproducibility of gene expression levels within or between different platforms, we propose a novel meta-analytic method that takes into account the vast amount of available probe-level information to combine the expression changes across different studies. We first show that the comparability of relative expression changes and the consistency of differentially expressed genes between different Affymetrix array generations can be considerably improved by determining the expression changes at the probe-level and by considering the latest information on probe-level sequence matching instead of the probe annotations provided by the manufacturer. With the improved probe-level expression change estimates, data from different generations of Affymetrix arrays can be combined more effectively. This will allow for the full exploitation of existing results when designing and analyzing new experiments.

Animals↗

PubMed2005

Quality classification of tandem mass spectrometry data.

UNLABELLED: Peptide identification by tandem mass spectrometry is an important tool in proteomic research. Powerful identification programs exist, such as SEQUEST, ProICAT and Mascot, which can relate experimental spectra to the theoretical ones derived from protein databases, thus removing much of the manual input needed in the identification process. However, the time-consuming validation of the peptide identifications is still the bottleneck of many proteomic studies. One way to further streamline this process is to remove those spectra that are unlikely to provide a confident or valid peptide identification, and in this way to reduce the labour from the validation phase. RESULTS: We propose a prefiltering scheme for evaluating the quality of spectra before the database search. The spectra are classified into two classes: spectra which contain valuable information for peptide identification and spectra that are not derived from peptides or contain insufficient information for interpretation. The different spectral features developed for the classification are tested on a real-life material originating from human lymphoblast samples and on a standard mixture of 9 proteins, both labelled with the ICAT-reagent. The results show that the prefiltering scheme efficiently separates the two spectra classes.

Algorithms↗

PubMed2005

Non-invasive respiratory monitoring during wakefulness and sleep in pre- and postmenopausal women.

Menopause and aging cause hormonal changes with respiratory consequences. The aim of the present study was to investigate the physiological changes in respiration during wakefulness and sleep across menopause in non-patient population using non-invasive measurements of blood and tissue gases. The arterial oxyhemoglobin saturation (SaO2), heart rate, end-tidal partial carbon dioxide tension (EtCO2) and transcutaneous partial carbon dioxide tension (TcCO2) were measured during wakefulness and sleep in thirteen pairs of BMI-matched pre- and postmenopausal women. Postmenopausal women had lower SaO2 during sleep than during wakefulness, whereas premenopausal women maintained their wakefulness SaO2 levels also during sleep. EtCO2 levels did not change either between wakefulness and sleep or between premenopausal and postmenopausal groups. TcCO2 levels increased from wakefulness to sleep in both groups and the increase was greater in the postmenopausal group. The impact of sleep on the non-invasive measurements of blood and tissue gases is stronger in postmenopausal women.

Adult↗

PubMed2005

Medroxyprogesterone improves nocturnal breathing in postmenopausal women with chronic obstructive pulmonary disease.

BACKGROUND: Progestins as respiratory stimulants in chronic obstructive pulmonary disease (COPD) have been investigated in males and during wakefulness. However, sleep and gender may influence therapeutic responses. We investigated the effects of a 2-week medroxyprogesterone acetate (MPA) therapy on sleep and nocturnal breathing in postmenopausal women. METHODS: A single-blind placebo-controlled trial was performed in 15 postmenopausal women with moderate to severe COPD. A 12-week trial included 2-week treatment periods with placebo and MPA (60 mg/d/14 days). All patients underwent a polysomnography with monitoring of SaO2 and transcutaneous PCO2 (tcCO2) at baseline, with placebo, with medroxyprogesterone acetate (MPA 60 mg/d/14 days), and three and six weeks after cessation of MPA. RESULTS: Thirteen patients completed the trial. At baseline, the average +/- SD of SaO2 mean was 90.6 +/- 3.2 % and the median of SaO2 nadir 84.8 % (interquartile range, IQR 6.1). MPA improved them by 1.7 +/- 1.6 %-units (95 % confidence interval (CI) 0.56, 2.8) and by 3.9 %-units (IQR 4.9; 95% CI 0.24, 10.2), respectively. The average of tcCO2 median was 6.0 +/- 0.9 kPa and decreased with MPA by 0.9 +/- 0.5 kPa (95% CI -1.3, -0.54). MPA improved SaO2 nadir and tcCO2 median also during REM sleep. Three weeks after cessation of MPA, the SaO2 mean remained 1.4 +/- 1.8 %-units higher than at baseline, the difference being not significant (95% CI -0.03, 2.8). SaO2 nadir was 2.7 %-units (IQR 4.9; 95% CI 0.06, 18.7) higher than at baseline. Increases in SaO2 mean and SaO2 nadir during sleep with MPA were inversely associated with baseline SaO2 mean (r = -0.70, p = 0.032) and baseline SaO2 nadir (r = -0.77, p = 0.008), respectively. Treatment response in SaO2 mean, SaO2 nadir and tcCO2 levels did not associate with pack-years smoked, age, BMI, spirometric results or sleep variables. CONCLUSION: MPA-induced respiratory improvement in postmenopausal women seems to be consistent and prolonged. The improvement was greater in patients with lower baseline SaO2 values. Long-term studies in females are warranted.

Aged↗

PubMed2005

Sleep quality, daytime sleepiness and fasting insulin levels in women with chronic obstructive pulmonary disease.

STUDY OBJECTIVES: To test the clinical observations that patients with chronic obstructive pulmonary disease (COPD) have impaired sleep quality without excessive daytime sleepiness (EDS), and to analyse the aetiological factors. PARTICIPANTS: Fifteen non-diabetic postmenopausal women with moderate to severe COPD and 20 community dwelling age-matched control women. MEASUREMENTS AND RESULTS: Patients completed questionnaires, had a polysomnography and blood tests. Controls filled in the questionnaires. In the Basic Nordic Sleep Questionnaire, the average (+/-sd) scores for sleepiness (9.9+/-3.0 in patients vs. 7.6+/-3.2 in controls, P = 0.025, test range 4-20) and insomnia (18.3+/-3.4 vs. 16.6+/-4.4, P = 123, test range 7-35) were low. Although 53% had a good night's sleep seldom or never and 70% slept restlessly, only 33% felt tired in the mornings. Controls reported better sleep quality, less tiredness and sleepiness. With polysomnography, the total sleep time was 4h 41 min +/-1h 20 min in patients. Sleep was fragmented, the proportion of stage 1 sleep high and rapid eye movement (REM) latency delayed. Sleepiness correlated with fasting serum insulin levels (r = 0.59, P = 0.027) and body movements (r = 0.52, P = 0.047). In stepwise linear regression analyses, sleepiness was positively associated with insulin levels (P = 0.025) but not with body movements. Insulin explained 38.0% of the variance in the sleepiness score, when adjusted for body mass index (BMI). CONCLUSIONS: Despite short and fragmented sleep, non-diabetic patients with COPD did not have marked EDS. An association between fasting insulin and sleepiness suggests that insulin resistance is involved in EDS.

Aged↗

PubMed2005

A comparative evaluation of software for the analysis of liquid chromatography-tandem mass spectrometry data from isotope coded affinity tag experiments.

The options available for processing quantitative data from isotope coded affinity tag (ICAT) experiments have mostly been confined to software specific to the instrument of acquisition. However, recent developments with data format conversion have subsequently increased such processing opportunities. In the present study, data sets from ICAT experiments, analysed with liquid chromatography/tandem mass spectrometry (MS/MS), using an Applied Biosystems QSTAR Pulsar quadrupole-TOF mass spectrometer, were processed in triplicate using separate mass spectrometry software packages. The programs Pro ICAT, Spectrum Mill and SEQUEST with XPRESS were employed. Attention was paid towards the extent of common identification and agreement of quantitative results, with additional interest in the flexibility and productivity of these programs. The comparisons were made with data from the analysis of a specifically prepared test mixture, nine proteins at a range of relative concentration ratios from 0.1 to 10 (light to heavy labelled forms), as a known control, and data selected from an ICAT study involving the measurement of cytokine induced protein expression in human lymphoblasts, as an applied example. Dissimilarities were detected in peptide identification that reflected how the associated scoring parameters favoured information from the MS/MS data sets. Accordingly, there were differences in the numbers of peptides and protein identifications, although from these it was apparent that both confirmatory and complementary information was present. In the quantitative results from the three programs, no statistically significant differences were observed.

Algorithms↗

PubMed2004

Statistical methods for identifying conserved residues in multiple sequence alignment.

The assessment of residue conservation in a multiple sequence alignment is a central issue in bioinformatics. Conserved residues and regions are used to determine structural and functional motifs or evolutionary relationships between the sequences of a multiple sequence alignment. For this reason, residue conservation is a valuable measure for database and motif search or for estimating the quality of alignments. In this paper, we present statistical methods for identifying conserved residues in multiple sequence alignments. While most earlier studies examine the positional conservation of the alignment, we focus on the detection of individual conserved residues at a position. The major advantages of multiple comparison methods originate from their ability to select conserved residues simultaneously and to consider the variability of the residue estimates. Large-scale simulations were used for the comparative analysis of the methods. Practical performance was studied by comparing the structurally and functionally important residues of Src homology 2 (SH2) domains to the assignments of the conservation indices. The applicability of the indices was also compared in three additional protein families comprising different degrees of entropy and variability in alignment positions. The results indicate that statistical multiple comparison methods are sensitive and reliable in identifying conserved residues.

Journal Article↗

PubMed2003

Efficient estimation of emission probabilities in profile hidden Markov models.

MOTIVATION: Profile hidden Markov models provide a sensitive method for performing sequence database search and aligning multiple sequences. One of the drawbacks of the hidden Markov model is that the conserved amino acids are not emphasized, but signal and noise are treated equally. For this reason, the number of estimated emission parameters is often enormous. Focusing the analysis on conserved residues only should increase the accuracy of sequence database search. RESULTS: We address this issue with a new method for efficient emission probability (EEP) estimation, in which amino acids are divided into effective and ineffective residues at each conserved alignment position. A practical study with 20 protein families demonstrated that the EEP method is capable of detecting family members from other proteins with sensitivity of 98% and specificity of 99% on the average, even if the number of free emission parameters was decreased to 15% of the original. In the database search for TIM barrel sequences, EEP recognizes the family members nearly as accurately as HMMER or Blast, but the number of false positive sequences was significantly less than that obtained with the other methods. AVAILABILITY: The algorithms written in C language are available on request from the authors.

Algorithms↗

PubMed2003

Identification of novel genes regulated by IL-12, IL-4, or TGF-beta during the early polarization of CD4+ lymphocytes.

Th1 and Th2 cells arise from a common precursor cell in response to triggering through the TCR and cytokine receptors for IL-12 or IL-4. This leads to activation of complex signaling pathways, which are not known in detail. Disturbances in the balance between type 1 and type 2 responses can lead to certain immune-mediated diseases. Thus, it is important to understand how Th1 and Th2 cells are generated. To clarify the mechanisms as to how IL-12 and IL-4 induce Th1 and Th2 differentiation and how TGF-beta can inhibit this process, we have used oligonucleotide arrays to examine the early polarization of Th1 and Th2 cells in the presence and absence of TGF-beta. In addition to genes previously implicated in the process, we have identified 20 genes with various known and unknown functions not previously associated with Th1/2 polarization. We have also further determined which genes are targets of IL-12, IL-4, and TGF-beta regulation in the cells induced to polarize to Th1 and Th2 directions. Interestingly, a subset of the genes was coregulated by IL-12 or IL-4 and TGF-beta. Among these genes are candidates that may modulate the balance between Th1 and Th2 responses.

Biomarkers↗

PubMed2003

Prediction of inspiratory flow shapes during sleep with a mathematic model of upper airway forces.

STUDY OBJECTIVES: To predict the airflow dynamics during sleep using a mathematic model that incorporates a number of static and dynamic upper airway forces, and to compare the numerical results to clinical flow data recorded from patients with sleep-disordered breathing on and off various treatment options. DESIGN: Upper airway performance was modeled in virtual subjects characterized by parameter settings that describe common combinations of risk factors predisposing to upper airway collapse during sleep. The treatments effect were induced by relevant changes of the initial parameter values. SETTING: Computer simulations at our website (http://www.utu.fi/ml/sovmat/bio/). PARTICIPANTS: Risk factors considered in the simulation settings were sex, obesity, pharyngeal collapsibility, and decreased phasic activity of pharyngeal muscles. INTERVENTIONS: The effects of weight loss, pharyngeal surgery, nasal continuous positive airway pressure, and respiratory stimulation on the inspiratory flow characteristics were tested with the model. MEASUREMENTS AND RESULTS: Numerical predictions were investigated by means of 3 measurable inspiratory airflow characteristics: initial slope, total volume, and flow shape. The model was able to reproduce the inspiratory flow shape characteristics that have previously been described in the literature. Simulation results also supported the observations that a multitude of factors underlie the pharyngeal collapse and, therefore, certain medical therapies that are effective in some conditions may prove ineffective in others. CONCLUSIONS: A mathematic model integrating the current knowledge of upper airway physiology is able to predict individual treatment responses. The model provides a framework for designing novel and potentially feasible treatment alternatives for sleep-disordered breathing.

Arousal↗

PubMed2003

Identification of novel IL-4/Stat6-regulated genes in T lymphocytes.

IL-4, primarily produced by T cells, mast cells, and basophiles, is a cytokine which has pleiotropic effects on the immune system. IL-4 induces T cells to differentiate to Th2 cells and activated B lymphocytes to proliferate and to synthesize IgE and IgG1. IL-4 is particularly important for the development and perpetuation of asthma and allergy. Stat6 is the protein activated by signal transduction through the IL-4R, and studies with knockout mice demonstrate that Stat6 is critical for a number of IL-4-mediated functions including Th2 development and production of IgE. In the present study, novel IL-4- and Stat6-regulated genes were discovered by using Stat6(-/-) mice and Affymetrix oligonucleotide arrays. Genes regulated by IL-4 were identified by comparing the gene expression profile of the wild-type T cells induced to polarize to the Th2 direction (CD3/CD28 activation + IL-4) to gene expression profile of the cells induced to proliferate (CD3/CD28 activation alone). Stat6-regulated genes were identified by comparing the cells isolated from the wild-type and Stat6(-/-) mice; in this experiment the cells were induced to differentiate to the Th2 direction (CD3/CD28 activation + IL-4). Our study demonstrates that a number a novel genes are regulated by IL-4 through Stat6-dependent and -independent pathways. Moreover, elucidation of kinetics of gene expression at early stages of cell differentiation reveals several genes regulated rapidly during the process, suggesting their importance for the differentiation process.

Animals↗

PubMed2003

Effect of medroxyprogesterone on inspiratory flow shapes during sleep in postmenopausal women.

We previously showed that medroxyprogesterone acetate (MPA) effectively decreases the arterial CO(2) levels in postmenopausal women with partial upper airway obstruction. The aim of the present study was to analyze the effects of MPA on the inspiratory flow shapes during sleep. Eight postmenopausal women with hypoxemia and partial upper airway obstruction during sleep (patients) received MPA 60 mg daily for 14 days. Four matched postmenopausal women without MPA treatment served as controls. Sleep and nasal pressure were recorded on each visit. Each breath was analyzed for duration, volume and inspiratory flow shape class. MPA shortened inspiration and prolonged expiration. The inspiratory volumes increased consistently in all flow shape classes. The inspiratory shapes with single late peak were transformed to those with double peak. MPA also decreased shapes with mid-peak or mid-plateau. MPA did not have an effect on sleep. Sleep modified the flow shape distribution only in patients but in a similar fashion in stages S2, SWS and REM. The results suggest that postmenopausal women present with a significant proportion breaths with poor initial inspiratory flow, which is reversed with MPA-induced respiratory stimulation.

Female↗

PubMed2003

Kinetics and STAT4- or STAT6-mediated regulation of genes involved in lymphocyte polarization to Th1 and Th2 cells.

Many genes implicated in Th1 and Th2 differentiation have been identified in both human and mouse. However, the functional roles and hierarchy of these factors in the signaling pathways leading to either Th1 or Th2 responses are less clear. To explore at which stage of polarization the differences between Th1 and Th2 cells occur, we have studied the expression of 23 key genes implicated in the process during the first week of polarization from human precursor T helper cells using quantitative real-time reverse transcription-PCR. According to our results, 14 of the genes were clearly regulated differentially in Th1 and Th2 conditions in distinct time-dependent patterns, either during the first 2 days or after 1 week of polarization. Furthermore, 6 of these genes were identified to be targets of STAT4/6 regulation. Thus, for the first time we demonstrate expression kinetics of a number of key genes involved in Th1 and Th2 differentiation during the first week of polarization in both human and mouse. In addition, our study shows for the first time that the genes BCL-6 and TRADD are differentially regulated during the polarization of human Th1 and Th2 cells.

Animals↗

PubMed2003

Comparison of PDQuest and Progenesis software packages in the analysis of two-dimensional electrophoresis gels.

Efficient analysis of protein expression by using two-dimensional electrophoresis (2-DE) data relies on the use of automated image processing techniques. The overall success of this research depends critically on the accuracy and the reliability of the analysis software. In addition, the software has a profound effect on the interpretation of the results obtained, and the amount of user intervention demanded during the analysis. The choice of analysis software that best meets specific needs is therefore of interest to the research laboratory. In this paper we compare two advanced analysis software packages, PDQuest and Progenesis. Their evaluation is based on quantitative tests at three different levels of standard 2-DE analysis: spot detection, gel matching and spot quantitation. As test materials we use three gel sets previously used in a similar comparison of Z3 and Melanie, and three sets of gels from our own research. It was observed that the quality of the test gels critically influences the spot detection and gel matching results. Both packages were sensitive to the parameter or filter settings with respect to the tendency of finding true positive and false positive spots. Quantitation results were very accurate for both analysis software packages.

Animals↗

PubMed2003

State of vigilance, oestrogen replacement therapy, and lipid profile as modifiers of nocturnal movement-induced heart rate responses.

STUDY OBJECTIVES: To investigate the body movement-associated heart rate responses during sleep in postmenopausal women and to evaluate the possible effect of transdermal oestrogen replacement therapy and metabolic factors on these responses. DESIGN: A prospective double-blind cross-over placebo-controlled trial. SETTING: A university sleep research unit. PATIENTS: Seventy-one healthy postmenopausal women. METHODS: The subjects underwent a whole-night polysomnography including an electrocardiogram (ECG) and a sensitive whole-body movement sensor channel. Body movements of 2-15 s duration with an artefact-free ECG were identified and heart rate was automatically analysed for 30 s before and 60 s after movement. The movement-induced reflex tachycardia and the following rebound bradycardia were measured for the awake state, non-rapid eye movement (REM) sleep and REM sleep. Indices of the heart rate response correlated with age, body mass index (BMI) and high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol ratio. RESULTS: The tachycardia response to a body movement was stronger during sleep than in the awake state, being strongest in REM sleep. The rebound bradycardia following a tachycardia response was relatively similar in REM and in the awake states, but attenuated in non-REM sleep. Oestrogen did not influence the heart rate response. Increasing age and BMI attenuated the response, while an increase in the HDL/LDL cholesterol ratio enhanced the rebound bradycardia response. CONCLUSIONS: Sleep powerfully modulates the rapid cardiac autonomic responses to internal stressors. Postmenopausal hormone replacement therapy does not influence these responses, but they are strongly modulated by lipid metabolism and closely correlated with age and BMI.

Aging↗

PubMed2003

Computational strategies for analyzing data in gene expression microarray experiments.

Microarray analysis has become a widely used method for generating gene expression data on a genomic scale. Microarrays have been enthusiastically applied in many fields of biological research, even though several open questions remain about the analysis of such data. A wide range of approaches are available for computational analysis, but no general consensus exists as to standard for microarray data analysis protocol. Consequently, the choice of data analysis technique is a crucial element depending both on the data and on the goals of the experiment. Therefore, basic understanding of bioinformatics is required for optimal experimental design and meaningful interpretation of the results. This review summarizes some of the common themes in DNA microarray data analysis, including data normalization and detection of differential expression. Algorithms are demonstrated by analyzing cDNA microarray data from an experiment monitoring gene expression in T helper cells. Several computational biology strategies, along with their relative merits, are overviewed and potential areas for additional research discussed. The goal of the review is to provide a computational framework for applying and evaluating such bioinformatics strategies. Solid knowledge of microarray informatics contributes to the implementation of more efficient computational protocols for the given data obtained through microarray experiments.

Algorithms↗