Top-down standards will not serve systems biology.
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Databases, Factual↗
Biomedical subjects
Rafael Irizarry
Publications and source records attributed to Rafael Irizarry.
On time series analysis of public health and biomedical data.
This paper gives an overview of time series ideas and methods used in public health and biomedical research. A time series is a sequence of observations made over time. Examples in public health include daily ozone concentrations, weekly admissions to an emergency department, or annual expenditures on health care in the United States. Time series models are most commonly used in regression analysis to describe the dependence of the response at each time on predictor variables including covariates and possibly previous values in the series. For example, Bell et al. ( 2 ) use time series methods to regress daily mortality in U.S. cities on concentrations of particulate air pollution. Time series methods are necessary to make valid inferences from data by accounting for the correlation among repeated responses over time.
Biomedical Research↗
Outcomes of adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas aeruginosa.
BACKGROUND: Although Pseudomonas aeruginosa is the most common bacterial infection in adults with cystic fibrosis and frequently develops resistance to multiple classes of antibiotics, it has not been determined whether patients with multiple antibiotic-resistant Pseudomonas aeruginosa have worse clinical outcomes than patients with more susceptible strains. OBJECTIVES: This study assessed the impact of multiply-resistant P. aeruginosa on lung function, hospitalizations, antibiotic use, lung transplantation and survival in adults with cystic fibrosis. METHODS: In a cohort study at a university-based adult cystic fibrosis program, 75 consecutive adult cystic fibrosis patients who had P. aeruginosa isolated from sputum cultures were studied over a 4-year period. Outcomes included decline in FEV1, clinic visits, hospitalizations, courses and days of intravenous antibiotics, and lung transplantation. Multiple linear and Poisson regression for repeated measures were used to assess the outcomes. RESULTS: In comparison to patients with susceptible strains, patients with resistant P. aeruginosa had more severe baseline lung disease, more rapid decline in FEV1 (160 ml/year, p = 0.003) and were significantly more likely to undergo lung transplantation (17.6 vs. 0%, p = 0.005). CONCLUSIONS: Infection with multiple-antibiotic-resistant P. aeruginosa is associated with accelerated progression of cystic fibrosis, and has important implications for infection control strategies, antibiotic use and lung transplantation.
Adult↗
Bioconductor: open software development for computational biology and bioinformatics.
The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.
Computational Biology↗
S-phase checkpoint genes safeguard high-fidelity sister chromatid cohesion.
Cohesion establishment and maintenance are carried out by proteins that modify the activity of Cohesin, an essential complex that holds sister chromatids together. Constituents of the replication fork, such as the DNA polymerase alpha-binding protein Ctf4, contribute to cohesion in ways that are poorly understood. To identify additional cohesion components, we analyzed a ctf4Delta synthetic lethal screen performed on microarrays. We focused on a subset of ctf4Delta-interacting genes with genetic instability of their own. Our analyses revealed that 17 previously studied genes are also necessary for the maintenance of robust association of sisters in metaphase. Among these were subunits of the MRX complex, which forms a molecular structure similar to Cohesin. Further investigation indicated that the MRX complex did not contribute to metaphase cohesion independent of Cohesin, although an additional role may be contributed by XRS2. In general, results from the screen indicated a sister chromatid cohesion role for a specific subset of genes that function in DNA replication and repair. This subset is particularly enriched for genes that support the S-phase checkpoint. We suggest that these genes promote and protect a chromatin environment conducive to robust cohesion.
Cell Cycle Proteins↗
Serum protein MALDI profiling to distinguish upper aerodigestive tract cancer patients from control subjects.
BACKGROUND: There are no reliable blood markers for the early detection and monitoring of aerodigestive tract tumors. Recent studies have suggested that serum protein patterns may be able to distinguish cancer patients from control subjects. METHODS: We used matrix-assisted laser desorption and ionization (MALDI) mass spectroscopy to obtain serum protein patterns from patients with head and neck cancer (n = 99) or lung cancer (n = 92) and from control subjects (n = 143) at risk for the development of these cancers. From the mass spectra, we predicted the cancer status of patients using a simple classification procedure based on a t test feature selection and linear discriminant analysis (LDA). We cross-validated the data with 200 random data simulations to establish a range of the LDA tuning parameter, which was used to construct receiver operating characteristic (ROC) curves. RESULTS: Average total protein levels were higher in case patients than in control subjects, although the differences were not statistically significant. Ten individual m/z peaks, from 5 to 111 kd, appeared frequently in head and neck cancer patients but not in control subjects. Using the 45 top predictors, selected by spectral mass and LDA, we observed that ROC curves differed from those expected under the null hypothesis, suggesting that spectral profiles from the sera of patients with head and neck cancer statistically significantly differed from the sera of control subjects. The model developed on head and neck cancer patients could also be used to identify patients with lung cancer. CONCLUSIONS: The pattern of protein spectra in total serum reliably distinguished cancer case patients from control subjects. Incorporation of MALDI assays into prospective longitudinal trials to assess the true predictive values of protein spectra in cancer detection is needed.
Adult↗
Unstable heart rate and temperature regulation predict mortality in AKR/J mice.
Elderly populations face greater risks of mortality when exposed to changes in environmental stress. The purpose of the following study was to develop an age-dependent susceptibility model that achieved the following three goals: 1) to operationally define homeostasis by assessing the stability and periodicity in physical activity, heart rate (HR), and deep body temperature (T(db)), 2) to specify alterations in activity, HR, and T(db) regulation that signal imminent death, and 3) to test the hypothesis that the decay in homeostasis associated with imminent death incorporates the coincident disintegration of multiple physiological systems. To achieve these goals, the circadian regulation of activity, HR, and T(db) was assessed using radiotelemeters implanted in AKR/J (n = 17) inbred mice at approximately 190 days of age. During a 12:12-h light-dark cycle, weekly measurements were obtained at 30-min intervals for 48-h periods until each animal's natural death. The average (+/-SE) life span of surgically treated animals did not differ from untreated controls (319 +/- 12 vs. 319 +/- 14 days). Cardiac and thermal stability were characterized by a circadian periodicity, which oscillated around stable daily averages of 640 +/- 14 beats/min in HR and 36.6 +/- 0.1 degrees C in T(db). Stable HR and T(db) responses were compared with extreme conditions 3 days before death, during which a disintegration of circadian periodicity was coincident with a fall in the daily average HR and T(db) of approximately 29 and approximately 13% lower (i.e., 456 +/- 22 beats/min and 31.7 +/- 0.6 degrees C), respectively. The results further suggested that multiple predictors of cardiac and thermal instability in AK mice, including significant bradycardia, hypothermia, and a loss of circadian periodicity, forecast life span 5-6 wk before expiration.
Animals↗
Circadian rhythm variation in activity, body temperature, and heart rate between C3H/HeJ and C57BL/6J inbred strains.
Inbred mice have been routinely used in studies of genetic effects that determine behavioral variation due to circadian rhythm. In addition to activity patterns (Act), we aimed to characterize variations in the circadian rhythm of deep-body temperature (T(db)) and heart rate (HR) in a specific genetic model of differential cardiorespiratory control. Radiotelemeters were implanted in C3H/HeJ (C3; n = 11) and C57BL/6J (B6; n = 11) inbred strains. Reciprocal first-generation offspring, B6C3F1/J (B6F1; n = 8) and C3B6F1 (C3F1; n = 3) mice, were included to initiate an evaluation of heritable phenotypes. Mice were housed individually in a facility maintained at 23-24 degrees C, and the light-dark cycle was set at 12-h intervals. In each animal, repeated measurements were obtained at 30-min intervals, and the circadian patterns of Act, T(db), and HR were assessed by novel statistical methods that detailed the periodic function for each strain. During the dark phase, B6 mice demonstrated two distinct peaks in Act and T(db) relative to a single early peak for C3 mice. In contrast to the parental strains, B6F1 and C3F1 mice demonstrated intermediate second peaks in Act and T(db). With respect to HR, the C3 strain demonstrated a significantly (P < 0.01) greater daily average compared with B6 mice. The circadian rhythm in HR differed significantly from the Act and T(db) patterns in B6 mice (but not in C3 mice); that is, the periodicity in HR for B6 mice preceded the rise and fall in Act and T(db) during both peaks. The B6 phenotype was also observed in F1 mice. In conclusion, these data suggest that the circadian regulation of Act, T(db), and HR vary significantly among C3, B6, and F1 mice. Furthermore, phenotypic differences between C3 and B6 strains can be used to explore the genetic basis for differential circadian regulation of body temperature and HR.
Activity Cycles↗