Statistical methods for analyzing gene expression data for cancer research.
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Animals↗
Biomedical subjects
N Friedman
Publications and source records attributed to N Friedman.
Evidence-based medicine: the key to guidelines, disease and care management programmes.
INTRODUCTION: Evidence-based medicine (EBM) is based on the concept of applying best practice to the diagnosis or treatment of a single patient or clinical question, one patient at one time. Although this is useful as a practitioner seeing patients one at a time, it is limited in its application to populations or to single patients with multiple diseases. I will review how to apply EBM to the structure and implementation of population-based care management programmes. METHODS: A review of the existing literature on the topic was undertaken in preparation for the First National Disease Management Conference-"Achieving seamless quality care across the continuum"-held between May 25 and 26, 2001. This material has been combined with experience and evidence of the author. RESULTS: EBM and practice form the basis of the development of evidence-based guidelines that help lay the path for populations of patients with specific conditions. Care and disease management are the programmes that have been developed to implement evidence-based guidelines and best practice and to produce optimal outcomes in populations with chronic conditions, either single or multiple. Examples are presented to further the understanding of the reader. CONCLUSIONS: To optimally improve the health of a population, chronic collaborative care programmes must be built and implemented that utilise best practice as defined by evidence in the literature.
Disease Management↗
Observation of islands of stability in soft wall atom-optics billiards.
We report on numerical and experimental observations of islands of stability induced in a Bunimovich stadium atom-optics billiard by a soft wall repulsive potential. A deviation from exponential decay of the survival probability of atoms in an open billiard is observed, and explained by the presence of these stable islands and a sticky region surrounding them. We also investigate islands in dispersing billiards with soft walls, and predict a new mechanism for their formation.
Journal Article↗
Caustic soda ingestion -- a case presentation and review of the literature.
We present a case report of a 2-year-old child with a hypopharyngeal stricture secondary to caustic soda ingestion. We discuss the initial and long-term management of caustic soda ingestion. In this case the hypopharynx was successfully reconstructed using a pedicled pectoralis major flap. We demonstrate the versatility of this flap, which is traditionally known for its use in adult head and neck surgery.
Administration, Oral↗
Observation of chaotic and regular dynamics in atom-optics billiards.
We report on experimental observations of chaotic and regular motion of ultracold atoms confined by a billiard-shaped optical dipole potential induced by a rapidly scanning laser beam. To investigate the dynamics of the atoms confined by such an "atom-optics" billiard we measure the decay of the number of trapped atoms through a hole on the boundary. A fast and purely exponential decay, the clear signature of chaotic motion, is found for a stadium billiard, but not for a circular or an elliptical billiard, in agreement with theory. We also investigated the effects of decoherence, velocity spread, and gravity on regular and chaotic motion.
Journal Article↗
Comparison of control of Listeria by nitric oxide redox chemistry from murine macrophages and NO donors: insights into listeriocidal activity of oxidative and nitrosative stress.
The physiological function of nitric oxide (NO) in the defense against pathogens is multifaceted. The exact chemistry by which NO combats intracellular pathogens such as Listeria monocytogenes is yet unresolved. We examined the effects of NO exposure, either delivered by NO donors or generated in situ within ANA-1 murine macrophages, on L. monocytogenes growth. Production of NO by the two NONOate compounds PAPA/NO (NH2(C3H6)(N[N(O)NO]C3H7) and DEA/NO (Na(C2H5)2N[N(O)NO]) resulted in L. monocytogenes cytostasis with minimal cytotoxicity. Reactive oxygen species generated from xanthine oxidase/hypoxanthine were neither bactericidal nor cytostatic and did not alter the action of NO. L. monocytogenes growth was also suppressed upon internalization into ANA-1 murine macrophages primed with interferon-gamma (INF-gamma) + tumor necrosis factor-alpha (TNF-alpha or INF-gamma + lipid polysaccharide (LPS). Growth suppression correlated with nitrite formation and nitrosation of 2,3-diaminonaphthalene elicited by stimulated murine macrophages. This nitrosative chemistry was not dependent upon nor mediated by interaction with reactive oxygen species (ROS), but resulted solely from NO and intermediates related to nitrosative stress. The role of nitrosation in controlling L. monocytogenes was further examined by monitoring the effects of exposure to NO on an important virulence factor, Listeriolysin O, which was inhibited under nitrosative conditions. These results suggest that nitrosative stress mediated by macrophages is an important component of the immunological arsenal in controlling L. monocytogenes infections.
2-Naphthylamine↗
Non-isomerizable artificial pigments: implications for the primary light-induced events in bacteriorhodopsin.
The primary events in the photosynthetic retinal protein bacteriorhodopsin (bR) are reviewed in light of photophysical and photochemical experiments with artificial bR in which the native retinal polyene is replaced by a variety of chromophores. Focus is on retinals in which the "critical" C13=C14 bond is locked with respect to isomerization by a rigid ring structure. Other systems include retinal oxime and non-isomerizable dyes noncovalently residing in the binding site. The early photophysical events are analyzed in view of recent pump-probe experiments with sub-picosecond time resolution comparing the behavior of bR pigments with those of model protonated Schiff bases in solution. An additional approach is based on the light-induced cleavage of the protonated Schiff base bond that links retinal to the protein by reacting with hydroxylamine. Also described are EPR experiments monitoring reduction and oxidation reactions of a spin label covalently attached to various protein sites. It is concluded that in bR the initial relaxation out of the Franck-Condon (FC) state does not involve substantial C13=C14 torsional motion and is considerably catalyzed by the protein matrix. Prior to the decay of the relaxed fluorescent state (FS or I state), the protein is activated via a mechanism that does not require double bond isomerization. Most plausibly, it is a result of charge delocalization in the excited state of the polyene (or other) chromophores. More generally, it is concluded that proteins and other macromolecules may undergo structural changes (that may affect their chemical reactivity) following optical excitation of an appropriately (covalently or non-covalently) bound chromophore. Possible relations between the light-induced changes due to charge delocalization, and those associated with C13=C14 isomerization (that are at the basis of the bR photocycle), are discussed. It is suggested that the two effects may couple at a certain stage of the photocycle, and it is the combination of the two that drives the cross-membrane proton pump mechanism.
Animals↗
Inferring subnetworks from perturbed expression profiles.
Genome-wide expression profiles of genetic mutants provide a wide variety of measurements of cellular responses to perturbations. Typical analysis of such data identifies genes affected by perturbation and uses clustering to group genes of similar function. In this paper we discover a finer structure of interactions between genes, such as causality, mediation, activation, and inhibition by using a Bayesian network framework. We extend this framework to correctly handle perturbations, and to identify significant subnetworks of interacting genes. We apply this method to expression data of S. cerevisiae mutants and uncover a variety of structured metabolic, signaling and regulatory pathways.
Bayes Theorem↗
Rich probabilistic models for gene expression.
Clustering is commonly used for analyzing gene expression data. Despite their successes, clustering methods suffer from a number of limitations. First, these methods reveal similarities that exist over all of the measurements, while obscuring relationships that exist over only a subset of the data. Second, clustering methods cannot readily incorporate additional types of information, such as clinical data or known attributes of genes. To circumvent these shortcomings, we propose the use of a single coherent probabilistic model, that encompasses much of the rich structure in the genomic expression data, while incorporating additional information such as experiment type, putative binding sites, or functional information. We show how this model can be learned from the data, allowing us to discover patterns in the data and dependencies between the gene expression patterns and additional attributes. The learned model reveals context-specific relationships, that exist only over a subset of the experiments in the dataset. We demonstrate the power of our approach on synthetic data and on two real-world gene expression data sets for yeast. For example, we demonstrate a novel functionality that falls naturally out of our framework: predicting the "cluster" of the array resulting from a gene mutation based only on the gene's expression pattern in the context of other mutations.
Algorithms↗
Evaluation of the consumer model: relationship between patients' expectations, perceptions and satisfaction with care.
OBJECTIVE: To evaluate the consumer model in a health care system, by studying the relationship between four variables: expectations, perceived degree of fulfillment, satisfaction and changing of physicians. DESIGN: Cross-sectional study; telephone interview of patients who had visited a primary care physician 1-2 months previously. SETTING: The Maccabi health plan, Israel. STUDY PARTICIPANTS: A random sample of 759 patients, aged 18 and over residing in two towns in Israel. Response rate to telephone interview was 50.7% (n=385). MAIN OUTCOME MEASURES: Expectation, perceived expectations fulfilled by the physician, satisfaction with the visit to the primary care physician and intention to change physician. RESULTS: The gap between the expectations and their fulfillment showed a low correlation with satisfaction. For attributes where a large difference was found, no correlation was found with patient satisfaction. Attributes such as 'diagnosis', 'preventive health care' and 'answering questions' presented correlation coefficients of 0.3. The correlation between the perceived fulfillment of these attributes and satisfaction presented higher correlation coefficients (between 0.4-0.5). This limits the consumer model as a way to predict satisfaction. Satisfaction correlated highly with intention to change physician. The mean score for the satisfaction of those intending to change doctors was 3.8 compared to 5.5 in the group of consumers not intending to change doctors. CONCLUSION: The consumer model is able to explain only to a modest extent the variation in satisfaction, but dissatisfaction is a good predictor of the intention to change doctors.
Adolescent↗
On the protein residues that control the yield and kinetics of O(630) in the photocycle of bacteriorhodopsin.
The effects of pH on the yield (phi(r)), and on the apparent rise and decay constants (k(r), k(d)), of the O(630) intermediate are important features of the bacteriorhodopsin (bR) photocycle. The effects are associated with three titration-like transitions: 1) A drop in k(r), k(d), and phi(r) at high pH [pK(a)(1) approximately 8]; 2) A rise in phi(r) at low pH [pK(a)(2) approximately 4.5]; and 3) A drop in k(r) and k(d) at low pH [pK(a)(3) approximately 4. 5]. (pK(a) values are for native bR in 100 mM NaCl). Clarification of these effects is approached by studying the pH dependence of phi(r), k(r), and k(d) in native and acetylated bR, and in its D96N and R82Q mutants. The D96N experiments were carried out in the presence of small amounts of the weak acids, azide, nitrite, and thiocyanate. Analysis of the mutant's data leads to the identification of the protein residue (R(1)) whose state of protonation controls the magnitude of phi(r), k(r), and k(d) at high pH, as Asp-96. Acetylation of bR modifies the Lys-129 residue, which is known to affect the pK(a) of the group (XH), which releases the proton to the membrane exterior during the photocycle. The effects of acetylation on the O(630) parameters reveal that the low-pH titrations should be ascribed to two additional protein residues R(2) and R(3). R(2) affects the rise of phi(r) at low pH, whereas the state of protonation of R(3) affects both k(r) and k(d). Our data confirm a previous suggestion that R(3) should be identified as the proton release moiety (XH). A clear identification of R(2), including its possible identity with R(3), remains open.
Amino Acid Substitution↗
Tissue classification with gene expression profiles.
Constantly improving gene expression profiling technologies are expected to provide understanding and insight into cancer-related cellular processes. Gene expression data is also expected to significantly aid in the development of efficient cancer diagnosis and classification platforms. In this work we examine three sets of gene expression data measured across sets of tumor(s) and normal clinical samples: The first set consists of 2,000 genes, measured in 62 epithelial colon samples (Alon et al., 1999). The second consists of approximately equal to 100,000 clones, measured in 32 ovarian samples (unpublished extension of data set described in Schummer et al. (1999)). The third set consists of approximately equal to 7,100 genes, measured in 72 bone marrow and peripheral blood samples (Golub et al, 1999). We examine the use of scoring methods, measuring separation of tissue type (e.g., tumors from normals) using individual gene expression levels. These are then coupled with high-dimensional classification methods to assess the classification power of complete expression profiles. We present results of performing leave-one-out cross validation (LOOCV) experiments on the three data sets, employing nearest neighbor classifier, SVM (Cortes and Vapnik, 1995), AdaBoost (Freund and Schapire, 1997) and a novel clustering-based classification technique. As tumor samples can differ from normal samples in their cell-type composition, we also perform LOOCV experiments using appropriately modified sets of genes, attempting to eliminate the resulting bias. We demonstrate success rate of at least 90% in tumor versus normal classification, using sets of selected genes, with, as well as without, cellular-contamination-related members. These results are insensitive to the exact selection mechanism, over a certain range.
Cluster Analysis↗
Using Bayesian networks to analyze expression data.
DNA hybridization arrays simultaneously measure the expression level for thousands of genes. These measurements provide a "snapshot" of transcription levels within the cell. A major challenge in computational biology is to uncover, from such measurements, gene/protein interactions and key biological features of cellular systems. In this paper, we propose a new framework for discovering interactions between genes based on multiple expression measurements. This framework builds on the use of Bayesian networks for representing statistical dependencies. A Bayesian network is a graph-based model of joint multivariate probability distributions that captures properties of conditional independence between variables. Such models are attractive for their ability to describe complex stochastic processes and because they provide a clear methodology for learning from (noisy) observations. We start by showing how Bayesian networks can describe interactions between genes. We then describe a method for recovering gene interactions from microarray data using tools for learning Bayesian networks. Finally, we demonstrate this method on the S. cerevisiae cell-cycle measurements of Spellman et al. (1998).
Algorithms↗
Determinants of hospital utilization: the situation in Israel and selected countries.
BACKGROUND: In 1995 hospital costs constituted about 42% of the health expenditures in Israel. Although this proportion remained stable over the last decade, hospital discharge rates per 1,000 population increased, while hospitalization days per 1,000 population and average length of stay declined. OBJECTIVE: To gain an insight into the forces behind these changes, we compared the trends in hospital utilization in Israel with those in 21 developed countries with available data. MATERIALS AND METHODS: Our data were derived from The "Hospitals and Day Care Units, 1995" report by the Health Information and Computer Services of the Israel Ministry of Health, and the Organization for Economic Cooperation and Development Health Data, 98. We examined the numbers of acute care hospital beds, of patients on dialysis and of doctors' consultations, health expenditures and age structure of the population in 1995 or closest year with available data, as well as changes in DRs, HDs and ALOS between 1976 and 1995. RESULTS: In Israel the DRs increased from 130 in 1976 to 177 in 1995 (36%), HDs declined from 992 to 818 (18%), and ALOS declined from 7.60 to 4.51 days (41%). Relative to other countries, in 1995 Israel had the lowest ALOS; low HDs similar to those in the UK, Portugal, Spain, the USA and Sweden; and intermediate DRs similar to those in Belgium, Germany, Sweden and Australia. The number of acute care beds per 1,000 population was directly related to HDs (r = 0.954, P = 0.000) and to DRs (r = 0.419, P = 0.052). Health expenditures (% of the gross national product) correlated with the number of patients on dialysis per 1,000,000 population (r = 0.743, P = 0.000). Between 1976 and 1995, HDs and ALOS declined in most countries, however the trends in DRs varied from an increase by 119% in the UK to a decline by 29% in Canada. CONCLUSIONS AND HYPOTHESES: The increase in DRs in Israel from 1976 to 1995 was shared by many but not all countries. This variability may be related to differences in trends in local practice norms and in available hospital beds. If the number of patients on dialysis is a valid index for use of expensive treatment modalities, the correlation of health expenditures with the number of patients on dialysis suggests that the use of expensive technology is a more important determinant of health care costs than the age of the population or hospital utilization. Since the use of expensive technology is highest during the first few days in hospital, decisions about health care policy should consider the possibility that the savings incurred by a further decline in HDs and ALOS may be offset by a possible increase in per diem hospital costs and in health care expenditures after discharge from hospital.
Australia↗
Generation of the O630 photointermediate of bacteriorhodopsin is controlled by the state of protonation of several protein residues.
The last stages of the photocycle of the photosynthetic pigment all-trans bacteriorhodopsin (bR570), as well as its proton pump mechanism, are markedly pH dependent. We have measured the relative amount of the accumulated O630 intermediate (Phir), as well as its rise and decay rate constants (kr and kd, respectively), over a wide pH range. The experiments were carried out in deionized membrane suspensions to which varying concentrations of metal cations and of large organic cations were added. The observed pH dependencies, s-shaped curves in the case of Phir and bell-shaped curves for kr and kd, are interpreted in terms of the titration of three protein residues denoted as R1, R2, and R3. The R1 titration is responsible for the increase in Phir, kr, and kd upon lowering the pH from pH approximately 9.5 to 7. At low pH Phir exhibits a secondary rise which is attributed to the titration of a low pKa group, R2. After reaching a maximum at pH approximately 7, kr and kd undergo a decrease upon decreasing the pH, which is attributed to the titration of R3. All three titrations exhibit pKa values which decrease upon increasing the salt concentration. As in the case of the Purple (bR570) if Blue (bR605) equilibrium, divalent cations are substantially more effective than monovalent cations in shifting the pKa values. Moreover, bulky organic cations are as effective as small metal cations. It is concluded that analogously to the Purple if Blue equilibrium, the salt binding sites which control the pKa values of R1, R2, and R3 are located on, or close to, the membrane surface. Possible identifications of the three protein residues are considered. Experiments with the E204Q mutant show that the mutation has markedly affected the R2 (Phir) titration, suggesting that R2 should be identified with Glu-204 or with a group whose pKa is affected by Glu-204. The relation between the R1, R2 and R3 titrations and the proton pump mechanism is discussed. It is evident that the pH dependence of Phir is unrelated to the measured pKa of the group (XH) which releases the proton to the extracellular medium during the photocycle. However, since the same residue may exhibit different pKa values at different stages of the photocycle, it cannot be excluded that R2 or R3 may be identified with XH.
Amino Acids↗
Rubber foam and staples: do they secure skin grafts? A model analysis and proposal of pressure enhancement techniques.
The significance of even pressure application and protection against shearing forces using a tie-over dressing of skin grafts has been stressed previously. Several methods for pressure enhancement have been described with no quantification or comparison between the different techniques. Rubber foam and metal staples are commonly used for simple and quick application of the dressings. We developed a model for analyzing the contact interface of the dressing with the skin graft and the pressure exerted by it. A stapled rubber foam tie-over dressing was compared with the original silk thread tie-over dressing. Six different embodiments were also analyzed, all constructed using only rubber foam and metal staples. Imprint and maximal projection analyses of the undersurfaces were performed. The original silk thread tie-over dressing exerted a relatively low pressure but was uniformly distributed. A regular stapled tie-over dressing applied a ring-shaped pressure with minimal projection. Other methods are described providing different contact areas with the grafts and different pressures.
Bandages↗
An evaluation of the iatrosedative process for treating dental fear.
The iatrosedative process is an interpersonal-cognitive technique by which fearful patients are calmed by the behavior, attitude, and communicative stance of the dentist. The process consists of an iatrosedative interview and a clinical encounter. In our study, 58 fearful dental patients were assigned to 1 of 3 treatment groups. The Corah Dental Anxiety Scale was administered at admission to the clinic, immediately after the iatrosedative interview or standard interview, and again after the first and second clinical encounters. Participants who received the iatrosedative interview had a significantly greater reduction in dental anxiety after the interview than those who received the standard interview. After the two clinical encounters, however, the difference in anxiety reduction between the two groups was not significant. In addition, there was no significant difference in anxiety reduction between iatrosedative participants who had the same dentist for both the interview and the clinical encounter and participants who had different dentists for each part of the study. It is concluded that an iatrosedative interview is more effective than a standard dental interview in decreasing anxiety.
Adult↗
Using a precision-metered injection system to minimize dental injection anxiety.
In this study, 90% of dental patients reported being at least mildly anxious about receiving dental injections. A new precision-metered injection system has been developed that can greatly increase the probability of painless injections of local anesthetic. Surveys were administered to patients to quantify their fears of dental injections and to measure the desensitization effect of using the new injection system. According to survey results, fear levels decreased significantly when the new technology was used.
Adult↗