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1.  Prediction of transplant-free survival in idiopathic pulmonary fibrosis patients using joint models for event times and mixed multivariate longitudinal data 
Journal of applied statistics  2014;41(10):2192-2205.
We implement a joint model for mixed multivariate longitudinal measurements, applied to the prediction of time until lung transplant or death in idiopathic pulmonary fibrosis. Specifically, we formulate a unified Bayesian joint model for the mixed longitudinal responses and time-to-event outcomes. For the longitudinal model of continuous and binary responses, we investigate multivariate generalized linear mixed models using shared random effects. Longitudinal and time-to-event data are assumed to be independent conditional on available covariates and shared parameters. A Markov chain Monte Carlo (MCMC) algorithm, implemented in OpenBUGS, is used for parameter estimation. To illustrate practical considerations in choosing a final model, we fit 37 different candidate models using all possible combinations of random effects and employ a Deviance Information Criterion (DIC) to select a best fitting model. We demonstrate the prediction of future event probabilities within a fixed time interval for patients utilizing baseline data, post-baseline longitudinal responses, and the time-to-event outcome. The performance of our joint model is also evaluated in simulation studies.
PMCID: PMC4157686  PMID: 25214700
Idiopathic Pulmonary Fibrosis; Joint model; Mixed continuous and binary data; Multivariate longitudinal data; Prediction model; Shared parameter model; Survival analysis
2.  The Secreted Proteins of Achlya hypogyna and Thraustotheca clavata Identify the Ancestral Oomycete Secretome and Reveal Gene Acquisitions by Horizontal Gene Transfer 
Genome Biology and Evolution  2014;7(1):120-135.
Saprotrophic and parasitic microorganisms secrete proteins into the environment to breakdown macromolecules and obtain nutrients. The molecules secreted are collectively termed the “secretome” and the composition and function of this set of proteins varies depending on the ecology, life cycle, and environment of an organism. Beyond the function of nutrient acquisition, parasitic lineages must also secrete molecules to manipulate their host. Here, we use a combination of de novo genome and transcriptome sequencing and bioinformatic identification of signal peptides to identify the putative secreted proteome of two oomycetes, the facultative parasite Achlya hypogyna and free-living Thraustotheca clavata. By comparing the secretomes of these saprolegnialean oomycetes with that of eight other oomycetes, we were able to characterize the evolution of this protein set across the oomycete clade. These species span the last common ancestor of the two major oomycete families allowing us to identify the ancestral secretome. This putative ancestral secretome consists of at least 84 gene families. Only 11 of these gene families are conserved across all 10 secretomes analyzed and the two major branches in the oomycete radiation. Notably, we have identified expressed elicitin-like effector genes in the saprotrophic decomposer, T. clavata. Phylogenetic analyses show six novel horizontal gene transfers to the oomycete secretome from bacterial and fungal donor lineages, four of which are specific to the Saprolegnialeans. Comparisons between free-living and pathogenic taxa highlight the functional changes of oomycete secretomes associated with shifts in lifestyle.
PMCID: PMC4316629  PMID: 25527045
oomycete; horizontal gene transfer; evolution; comparative genomics; osmotrophy
3.  Peripheral Blood Mononuclear Cell Gene Expression Profiles Predict Poor Outcome in Idiopathic Pulmonary Fibrosis 
Science translational medicine  2013;5(205):205ra136.
We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. We studied the pathways associated with TFS in each independent microarray cohort and identified decreased expression of “The costimulatory signal during T cell activation” Biocarta pathway and, in particular, the genes CD28, ICOS, LCK, and ITK, results confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient’s age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4+CD28+ T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.
PMCID: PMC4175518  PMID: 24089408
4.  Complex Patterns of Gene Fission in the Eukaryotic Folate Biosynthesis Pathway 
Genome Biology and Evolution  2014;6(10):2709-2720.
Shared derived genomic characters can be useful for polarizing phylogenetic relationships, for example, gene fusions have been used to identify deep-branching relationships in the eukaryotes. Here, we report the evolutionary analysis of a three-gene fusion of folB, folK, and folP, which encode enzymes that catalyze consecutive steps in de novo folate biosynthesis. The folK-folP fusion was found across the eukaryotes and a sparse collection of prokaryotes. This suggests an ancient derivation with a number of gene losses in the eukaryotes potentially as a consequence of adaptation to heterotrophic lifestyles. In contrast, the folB-folK-folP gene is specific to a mosaic collection of Amorphea taxa (a group encompassing: Amoebozoa, Apusomonadida, Breviatea, and Opisthokonta). Next, we investigated the stability of this character. We identified numerous gene losses and a total of nine gene fission events, either by break up of an open reading frame (four events identified) or loss of a component domain (five events identified). This indicates that this three gene fusion is highly labile. These data are consistent with a growing body of data indicating gene fission events occur at high relative rates. Accounting for these sources of homoplasy, our data suggest that the folB-folK-folP gene fusion was present in the last common ancestor of Amoebozoa and Opisthokonta but absent in the Metazoa including the human genome. Comparative genomic data of these genes provides an important resource for designing therapeutic strategies targeting the de novo folate biosynthesis pathway of a variety of eukaryotic pathogens such as Acanthamoeba castellanii.
PMCID: PMC4224340  PMID: 25252772
phylogenetics; comparative genomics; pterin biosynthesis; Diaphoretickes
5.  Pneumocystis jirovecii colonization is associated with enhanced Th1 inflammatory gene expression in lungs of humans with chronic obstructive pulmonary disease 
Microbiology and immunology  2014;58(3):202-211.
Chronic obstructive pulmonary disease (COPD) is a complex disease, the pathogenesis of which remains incompletely understood. Colonization with Pneumocystis jirovecii may play a role in COPD pathogenesis; however, the mechanisms by which such colonization contributes to COPD are unknown. The objective of this study was to determine lung gene expression profiles associated with Pneumocystis colonization in patients with COPD to identify potential key pathways involved in disease pathogenesis. Using COPD lung tissue samples made available through the Lung Tissue Research Consortium (LTRC), Pneumocystis colonization status was determined by nested PCR. Microarray gene expression profiles were performed for each sample and the profiles of colonized and non-colonized samples compared. Overall, 18 participants (8.5%) were Pneumocystis-colonized. Pneumocystis colonization was associated with fold increase in expression of four closely related genes: INF-γ and the three chemokine ligands CXCL9, CXCL10, and CXCL11. These ligands are chemoattractants for the common cognate receptor CXCR3, which is predominantly expressed on activated Th1 T-lymphocytes. Although these ligand–receptor pairs have previously been implicated in COPD pathogenesis, few initiators of ligand expression and subsequent lymphocyte trafficking have been identified: our findings implicate Pneumocystis as a potential trigger. The finding of upregulation of these inflammatory genes in the setting of Pneumocystis colonization sheds light on infectious-immune relationships in COPD.
PMCID: PMC4106795  PMID: 24438206
chronic obstructive; microarray; Pneumocystis jirovecii; Pulmonary disease; Th1 cells
6.  Doctor shopping by overweight and obese patients is associated with increased healthcare utilization 
Obesity (Silver Spring, Md.)  2013;21(7):1328-1334.
Negative interactions with healthcare providers may lead patients to switch physicians or “doctor shop.” We hypothesized that overweight and obese patients would be more likely to doctor shop, and as a result, have increased rates of emergency department (ED) visits and hospitalizations as compared to normal weight non-shoppers. We combined claims data from a health plan in one state with information from beneficiaries’ health risk assessments. The primary outcome was “doctor shopping,” which we defined as having outpatient claims with ≥5 different primary care physicians (PCPs) during a 24-month period. The independent variable was standard NIH categories of weight by BMI. We performed multivariate logistic regression to evaluate the association between weight categories and doctor shopping. We conducted multivariate zero-inflated negative binominal regression to evaluate the association between weight-doctor shopping categories with counts of ED visits and hospitalizations. Of the 20,726 beneficiaries, the mean BMI was 26.3 kg/m2 (SD 5.1), mean age was 44.4 years (SD 11.1) and 53% were female. As compared to normal weight beneficiaries, overweight beneficiaries had 23% greater adjusted odds of doctor shopping (OR 1.23, 95%CI 1.04–1.46) and obese beneficiaries had 52% greater adjusted odds of doctor shopping (OR 1.52, 95%CI 1.26–1.82). As compared to normal weight non-shoppers, overweight and obese shoppers had higher rates of ED visits (IRR 1.85, 95%CI 1.37–2.45; IRR 1.83, 95%CI 1.34–2.50, respectively), which persisted during within weight group comparisons (Overweight IRR 1.50, 95%CI 1.10–2.03; Obese IRR 1.54, 95%CI 1.12–2.11). Frequently changing PCPs may impair continuity and result in increased healthcare utilization.
PMCID: PMC3742565  PMID: 23671015
7.  A Rhodopsin-Guanylyl Cyclase Gene Fusion Functions in Visual Perception in a Fungus 
Current Biology  2014;24(11):1234-1240.
Sensing light is the fundamental property of visual systems, with vision in animals being based almost exclusively on opsin photopigments [1]. Rhodopsin also acts as a photoreceptor linked to phototaxis in green algae [2, 3] and has been implicated by chemical means as a light sensor in the flagellated swimming zoospores of the fungus Allomyces reticulatus [4]; however, the signaling mechanism in these fungi remains unknown. Here we use a combination of genome sequencing and molecular inhibition experiments with light-sensing phenotype studies to examine the signaling pathway involved in visual perception in the closely related fungus Blastocladiella emersonii. Our data show that in these fungi, light perception is accomplished by the function of a novel gene fusion (BeGC1) of a type I (microbial) rhodopsin domain and guanylyl cyclase catalytic domain. Photobleaching of rhodopsin function prevents accumulation of cGMP levels and phototaxis of fungal zoospores exposed to green light, whereas inhibition of guanylyl cyclase activity negatively affects fungal phototaxis. Immunofluorescence microscopy localizes the BeGC1 protein to the external surface of the zoospore eyespot positioned close to the base of the swimming flagellum [4, 5], demonstrating this is a photoreceptive organelle composed of lipid droplets. Taken together, these data indicate that Blastocladiomycota fungi have a cGMP signaling pathway involved in phototaxis similar to the vertebrate vision-signaling cascade but composed of protein domain components arranged as a novel gene fusion architecture and of distant evolutionary ancestry to type II rhodopsins of animals.
•A rhodopsin-guanylate cyclase gene fusion is involved in B. emersonii phototaxis•The rhodopsin fusion protein BeGC1 is localized to the zoospore eyespot apparatus•Endogenous retinal substitution by retinalA1 reconstitutes green light phototaxis•Zoospore phototaxis uses cGMP as a second messenger similar to vertebrate vision
Avelar et al. use genome sequencing, molecular inhibition, and light-sensing phenotype experiments, combined with immunolocalization data, to show that a type I rhodopsin-guanylyl cyclase fusion protein localizes to the “eyespot” and is involved in green light phototaxis in zoospores of the Blastocladiomycete fungus Blastocladiella emersonii.
PMCID: PMC4046227  PMID: 24835457
8.  Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study 
The lancet. Respiratory medicine  2013;1(4):309-317.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF.
First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10−8) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes.
In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r2=0.07], rs5743894 [r2=0.16], and rs5743890 [r2=0.01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1.72 [95% CI 1.24–2.38]; p=0.0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0.097), 40% in those with the minor allele of rs111521887 (p=3.0 × 10−4), and 50% in those with the minor allele of rs5743894 (p=2.93 × 10−5) compared with homozygous carriers of common alleles for these SNPs.
Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease.
National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.
PMCID: PMC3894577  PMID: 24429156
9.  Clinical Outcomes after Bariatric Surgery: A Five-Year Matched Cohort Analysis in Seven US States 
Obesity surgery  2012;22(5):749-763.
Bariatric surgery is the most effective weight loss treatment, yet few studies have reported on short- and long-term outcomes postsurgery.
Using claims data from seven Blue Cross/Blue Shield health plans serving seven states, we conducted a non-concurrent, matched cohort study. We followed 22,693 persons who underwent bariatric surgery during 2003–2007 and were enrolled at least 6 months before and after surgery. Using logistic regression, we compared serious and less serious adverse clinical outcomes, hospitalizations, planned procedures, and obesity-related co-morbidities between groups for up to 5 years.
Relative to controls, surgery patients were more likely to experience a serious [odds ratio (OR) 1.9; 95% confidence interval (CI) 1.8–2.0] or less serious (OR 2.5, CI 2.4–2.7) adverse clinical outcome or hospitalization (OR 1.3, CI 1.3–1.4) at 1 year postsurgery. The risk remained elevated until 4 years postsurgery for serious events and 5 years for less serious outcomes and hospitalizations. Some complication rates were lower for patients undergoing laparoscopic surgery. Planned procedures, such as skin reduction, peaked in postsurgery year 2 but remained elevated through year 5. Surgery patients had a 55% decreased risk of obesity-related co-morbidities, such as type 2 diabetes, in the first year postsurgery, which remained low throughout the study (year 5: OR 0.4, CI 0.4–0.5).
While bariatric surgery is associated with a higher risk of adverse clinical outcomes compared to controls, it also substantially decreased obesity-related co-morbidities during the 5-year follow-up.
PMCID: PMC4040221  PMID: 22271357
Cohort study; Obesity treatment; Bariatric surgery; Outcomes; Complications
10.  Diverse molecular signatures for ribosomally ‘active’ Perkinsea in marine sediments 
BMC Microbiology  2014;14:110.
Perkinsea are a parasitic lineage within the eukaryotic superphylum Alveolata. Recent studies making use of environmental small sub-unit ribosomal RNA gene (SSU rDNA) sequencing methodologies have detected a significant diversity and abundance of Perkinsea-like phylotypes in freshwater environments. In contrast only a few Perkinsea environmental sequences have been retrieved from marine samples and only two groups of Perkinsea have been cultured and morphologically described and these are parasites of marine molluscs or marine protists. These two marine groups form separate and distantly related phylogenetic clusters, composed of closely related lineages on SSU rDNA trees. Here, we test the hypothesis that Perkinsea are a hitherto under-sampled group in marine environments. Using 454 diversity ‘tag’ sequencing we investigate the diversity and distribution of these protists in marine sediments and water column samples taken from the Deep Chlorophyll Maximum (DCM) and sub-surface using both DNA and RNA as the source template and sampling four European offshore locations.
We detected the presence of 265 sequences branching with known Perkinsea, the majority of them recovered from marine sediments. Moreover, 27% of these sequences were sampled from RNA derived cDNA libraries. Phylogenetic analyses classify a large proportion of these sequences into 38 cluster groups (including 30 novel marine cluster groups), which share less than 97% sequence similarity suggesting this diversity encompasses a range of biologically and ecologically distinct organisms.
These results demonstrate that the Perkinsea lineage is considerably more diverse than previously detected in marine environments. This wide diversity of Perkinsea-like protists is largely retrieved in marine sediment with a significant proportion detected in RNA derived libraries suggesting this diversity represents ribosomally ‘active’ and intact cells. Given the phylogenetic range of hosts infected by known Perkinsea parasites, these data suggest that Perkinsea either play a significant but hitherto unrecognized role as parasites in marine sediments and/or members of this group are present in the marine sediment possibly as part of the ‘seed bank’ microbial community.
PMCID: PMC4044210  PMID: 24779375
454 pyrosequencing; Perkinsus; Parvilucifera; Food web; Protist; Parasite
11.  Evolution and Classification of Myosins, a Paneukaryotic Whole-Genome Approach 
Genome Biology and Evolution  2014;6(2):290-305.
Myosins are key components of the eukaryotic cytoskeleton, providing motility for a broad diversity of cargoes. Therefore, understanding the origin and evolutionary history of myosin classes is crucial to address the evolution of eukaryote cell biology. Here, we revise the classification of myosins using an updated taxon sampling that includes newly or recently sequenced genomes and transcriptomes from key taxa. We performed a survey of eukaryotic genomes and phylogenetic analyses of the myosin gene family, reconstructing the myosin toolkit at different key nodes in the eukaryotic tree of life. We also identified the phylogenetic distribution of myosin diversity in terms of number of genes, associated protein domains and number of classes in each taxa. Our analyses show that new classes (i.e., paralogs) and domain architectures were continuously generated throughout eukaryote evolution, with a significant expansion of myosin abundance and domain architectural diversity at the stem of Holozoa, predating the origin of animal multicellularity. Indeed, single-celled holozoans have the most complex myosin complement among eukaryotes, with paralogs of most myosins previously considered animal specific. We recover a dynamic evolutionary history, with several lineage-specific expansions (e.g., the myosin III-like gene family diversification in choanoflagellates), convergence in protein domain architectures (e.g., fungal and animal chitin synthase myosins), and important secondary losses. Overall, our evolutionary scheme demonstrates that the ancestral eukaryote likely had a complex myosin repertoire that included six genes with different protein domain architectures. Finally, we provide an integrative and robust classification, useful for future genomic and functional studies on this crucial eukaryotic gene family.
PMCID: PMC3942036  PMID: 24443438
origin of eukaryotes; LECA; Holozoa; eukaryote evolution; chitin synthase; Smad
12.  Cartilage Oligomeric Matrix Protein in Idiopathic Pulmonary Fibrosis 
PLoS ONE  2013;8(12):e83120.
Idiopathic pulmonary fibrosis (IPF) is a progressive and life threatening disease with median survival of 2.5–3 years. The IPF lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein (COMP), a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes (Fold change 13, p-value <0.05) in IPF lungs. This finding was confirmed at the mRNA level by nCounter® expression analysis in additional 115 IPF lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of IPF lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-β1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-β1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of IPF patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity (FVC). Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-β1 activity in patients with IPF. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in IPF and interfere with the amplification of TGF-β1 signaling should be persuaded.
PMCID: PMC3869779  PMID: 24376648
13.  Use of lung cancer screening tests in the United States: results from the 2010 National Health Interview Survey 
Prior to evidence of efficacy, lung cancer screening was being ordered by many physicians. The National Lung Screening Trial (NLST), which demonstrated a 20 percent reduction in lung cancer mortality among those randomized to receive low-dose computed tomography (LDCT), will likely lead to increased screening use.
We estimated the prevalence of chest x-ray and CT use in the United States using data from the 2010 National Health Interview Survey (NHIS). Subjects included 15,537 NHIS respondents aged ≥40 years without prior diagnosis of lung cancer. Estimates of the size of the U. S. population by age and smoking status were calculated. Multivariate logistic regression examined predictors of test use adjusting for potential confounders.
Twenty-three percent of adults reported chest x-ray in the previous year, and 2.5 percent reported chest x-ray specifically to check for lung cancer; corresponding numbers for chest CT were 7.5 and 1.3 percent. Older age, black race, male gender, smoking, respiratory disease, personal history of cancer, and having health insurance were associated with test use. Approximately 8.7 million adults in the United States would be eligible for LDCT screening according to NLST eligibility criteria.
Conclusions and Impact
Monitoring of trends in the use of lung screening tests will be vital to assess the impact of NLST and possible changes in lung cancer screening recommendations and insurance coverage in the future. Education of patients by their physicians, and of the general public, may help ensure that screening is used appropriately, in those most likely to benefit.
PMCID: PMC3392469  PMID: 22573798
lung cancer; screening; chest x-ray; low-dose helical computed tomography; national survey
14.  Multi-Institutional Sharing of Electronic Health Record Data to Assess Childhood Obesity 
PLoS ONE  2013;8(6):e66192.
To evaluate the validity of multi-institutional electronic health record (EHR) data sharing for surveillance and study of childhood obesity.
We conducted a non-concurrent cohort study of 528,340 children with outpatient visits to six pediatric academic medical centers during 2007–08, with sufficient data in the EHR for body mass index (BMI) assessment. EHR data were compared with data from the 2007–08 National Health and Nutrition Examination Survey (NHANES).
Among children 2–17 years, BMI was evaluable for 1,398,655 visits (56%). The EHR dataset contained over 6,000 BMI measurements per month of age up to 16 years, yielding precise estimates of BMI. In the EHR dataset, 18% of children were obese versus 18% in NHANES, while 35% were obese or overweight versus 34% in NHANES. BMI for an individual was highly reliable over time (intraclass correlation coefficient 0.90 for obese children and 0.97 for all children). Only 14% of visits with measured obesity (BMI ≥95%) had a diagnosis of obesity recorded, and only 20% of children with measured obesity had the diagnosis documented during the study period. Obese children had higher primary care (4.8 versus 4.0 visits, p<0.001) and specialty care (3.7 versus 2.7 visits, p<0.001) utilization than non-obese counterparts, and higher prevalence of diverse co-morbidities. The cohort size in the EHR dataset permitted detection of associations with rare diagnoses. Data sharing did not require investment of extensive institutional resources, yet yielded high data quality.
Multi-institutional EHR data sharing is a promising, feasible, and valid approach for population health surveillance. It provides a valuable complement to more resource-intensive national surveys, particularly for iterative surveillance and quality improvement. Low rates of obesity diagnosis present a significant obstacle to surveillance and quality improvement for care of children with obesity.
PMCID: PMC3688837  PMID: 23823186
15.  Impact of Bariatric Surgery on Healthcare Utilization and Costs among Patients with Diabetes 
Medical care  2012;50(1):58-65.
The effect of bariatric surgery on health care utilization and costs among individuals with type 2 diabetes remains unclear.
To examine healthcare utilization and costs in an insured cohort of individuals with type 2 diabetes after bariatric surgery.
Research Design
Cohort study derived from administrative data from 2002–2008 from 7 Blue Cross Blue Shield Plans.
7,806 individuals with type 2 diabetes who had bariatric surgery
Cost (inpatient, outpatient, pharmacy, other) and utilization (number of inpatient days, outpatient visits, specialist visits).
Compared to pre-surgical costs, the ratio of hospital costs (excluding the initial surgery), among beneficiaries who had any hospital costs, was higher in years 2 through 6 of the post-surgery period and increased over time [post 1: OR = 0.58 (95% CI: 0.50, 0.67); post 6: OR = 3.43 (95% CI: 2.60, 4.53)]. In comparison to the pre-surgical period, the odds of having any healthcare costs was lower in the post-surgery period and remained relatively flat over time. Among those with hospitalizations, the adjusted ratio of inpatient days was higher after surgery [post 1: OR = 1.05 (95% CI: 0.94, 1.16); post 6: OR = 2.77 (95% CI: 1.57, 4.90)]. Among those with primary care visits, the adjusted odds ratio was lower after surgery [post 1: OR = 0.80 (95% CI: 0.78, 0.82); post 6: OR = 0.66 (95% CI: 0.57, 0.76)].
In the six years following surgery, individuals with type 2 diabetes did not have lower healthcare costs than before surgery.
PMCID: PMC3241012  PMID: 22167064
16.  Peripheral Blood Proteins Predict Mortality in Idiopathic Pulmonary Fibrosis 
Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course.
Objectives: The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF.
Methods: Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested.
Measurements and Main Results: High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort.
Conclusions: Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.
PMCID: PMC3262037  PMID: 22016448
MMP-7; adhesion molecules; biomarkers; personalized medicine; mortality prediction
17.  Association between cutaneous melanoma incidence rates among white U.S. residents and county-level estimates of solar ultraviolet exposure 
Recent U.S. studies have raised questions as to whether geographic differences in cutaneous melanoma incidence rates are associated with differences in solar ultraviolet (UV) exposure.
To assess the association of solar UV exposure with melanoma incidence rates among U.S. non-Hispanic whites.
We assessed the association between county-level estimates of average annual solar UV exposure for 1961–1990 and county-level melanoma incidence rates during 2004–2006. We used Poisson multilevel mixed models to calculate incidence density ratios by cancer stage at diagnosis while controlling for individuals' age and sex and for county-level estimates of solar UV exposure, socioeconomic status, and physician density.
Age-adjusted rates of early- and late-stage melanoma were both significantly higher in high solar UV counties than in low solar UV counties. Rates of late-stage melanoma incidence were generally higher among men, but younger women had a higher rate of early-stage melanoma than their male counterparts. Adjusted rates of early-stage melanoma were significantly higher in high solar UV exposure counties among men aged 35 or older and women aged 65 or older.
The relationship between individual-level UV exposure and risk for melanoma was not evaluated.
County-level solar UV exposure was associated with the incidence of early-stage melanoma among older U.S. adults but not among younger U.S. adults. Additional studies are needed to determine whether exposure to artificial sources of UV exposure or other factors might be mitigating the relationship between solar UV exposure and risk for melanoma.
PMCID: PMC3206292  PMID: 22018067
solar ultraviolet rays/adverse effects; melanoma/epidemiology; skin neoplasms/epidemiology; population surveillance; incidence; registries; socioeconomic factors; dermatology/manpower
18.  Discussions About Prostate Cancer Screening Between U.S. Primary Care Physicians and Their Patients 
Journal of General Internal Medicine  2011;26(10):1098-1104.
This study examined the likelihood that U.S. primary care physicians (PCPs) discuss and recommend prostate cancer screening with their patients and physician-related and practice-related factors associated with this behavior.
We analyzed data from the 2007–2008 National Survey of Primary Care Physician Practices Regarding Prostate Cancer Screening (N = 1,256), the most recent and comprehensive survey specifically designed to address issues concerning prostate cancer screening and representing nearly 95,000 PCPs. We evaluated the relationship between PCP behavior regarding prostate cancer screening discussions and covariates, including PCP demographic and practice-related factors. Weighted percentages and Chi-square tests were used to compare use of screening discussions by PCP characteristics. Adjusted odds of discussing screening and recommending the PSA test were determined from logistic regression.
Eighty percent of PCPs reported that they routinely discuss prostate cancer screening with all of their male patients, and 64.1% of PCPs who discussed screening with any patients reported that they attempted to talk their patients into getting the PSA test. In multivariate analyses, encouraging PSA testing was more likely among non-Hispanic black PCPs (OR = 2.80, 95% CI [1.88, 4.16]), PCPs serving 100 or more patients per week (OR = 2.16, 95% CI [1.38, 3.37]), and PCPs spending longer hours per week in direct patient care (31–40 hours: OR = 1.90, 95% CI [1.13, 3.20]; 41 or more hours: OR = 2.09, 95% CI [1.12, 3.88]), compared to their referents. PCPs in multi-specialty group practice were more likely to remain neutral or discourage PSA testing compared to PCPs in solo practice.
Both individual and practice-related factors of PCPs were associated with the use of prostate cancer screening discussions by U.S. PCPs. Results from this study may prove valuable to researchers and clinicians and help guide the development and implementation of future prostate cancer screening interventions in the U.S.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-011-1682-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3181308  PMID: 21416405
primary care physicians; prostate cancer screening; prostate-specific antigen; physician–patient discussions; prostate cancer
19.  Prostate cancer screening practices of African-American and non-African-American US primary care physicians: a cross-sectional survey 
We explored whether African-American (AA) primary care physicians (PCPs) have different prostate cancer screening practices compared to non-AA PCPs, after adjustment for potential confounding factors such as the proportion of AA patients in PCP practices.
We used SAS/SUDAAN to compare weighted responses from AA PCPs (n = 604) with those from non-AA PCPs (n = 647) in the 2007–2008 National Survey of Primary Care Physician Practices Regarding Prostate Cancer Screening. We used multivariate logistic regression to calculate the weighted odds ratios (OR) and 95% confidence intervals (CI).
We found that AA PCPs had higher odds of working in practices with above-the-median (≥ 21%) proportions of AA male patients (OR, 9.02; 95% CI: 5.85–13.91). A higher proportion of AA PCPs (53.5%; 95% CI: 49.5–57.4) reported an above-the-median proportion (≥ 91%) of PSA testing during health maintenance exams as compared to non-AA PCPs (39.4%; 95% CI: 35.5–43.4; P < 0.0002). After adjusting for the proportion of AA patients and other factors, we found that AA PCPs had higher odds of using PSA tests to screen men (OR, 1.74; 95% CI: 1.11–2.73).
This study quantifies the magnitude of the differences reported in previous focus group studies. Our results may be helpful in hypothesis generation and in planning future research studies.
PMCID: PMC3459664  PMID: 23049271
African-American; physician practice patterns; prostate-specific antigen; screening tests
20.  Validation and justification of the phylum name Cryptomycota phyl. nov. 
The recently proposed new phylum name Cryptomycota phyl. nov. is validly published in order to facilitate its use in future discussions of the ecology, biology, and phylogenetic relationships of the constituent organisms. This name is preferred over the previously tentatively proposed “Rozellida” as new data suggest that the life-style and morphology of Rozella is not representative of the large radiation to which it and other Cryptomycota belong. Furthermore, taxa at higher ranks such as phylum are considered better not based on individual names of included genera, but rather on some special characteristics – in this case the cryptic nature of this group and that they were initially revealed by molecular methods rather than morphological discovery. If the group were later viewed as a member of a different kingdom, the name should be retained to indicate its fungal affinities, as is the practice for other fungal-like protist groups.
PMCID: PMC3359815  PMID: 22679602
chitin; chytrid; Fungi; phylogeny; Rozella; Rozellida
21.  U.S. Primary Care Physicians’ Lung Cancer Screening Beliefs and Recommendations 
No high-quality study to date has shown that screening reduces lung cancer mortality, and expert groups do not recommend screening for asymptomatic individuals. Nevertheless, lung cancer screening tests are available in the U.S., and primary care physicians (PCPs) may have a role in recommending them to patients.
This study describes U.S. PCPs’ beliefs about and recommendations for lung cancer screening, and examines characteristics of PCPs who recommend screening.
A nationally representative survey of practicing PCPs was conducted in 2006–2007. Mailed questionnaires assessed PCPs’ beliefs about lung cancer screening guidelines and the effectiveness of screening tests, and whether PCPs would recommend screening for asymptomatic patients. Data were analyzed in 2009.
Nine hundred and sixty-two PCPs completed the survey (absolute response rate=70.6%; cooperation rate=76.8%). One quarter said that major guidelines support lung cancer screening. Two thirds said that low–radiation dose spiral CT (LDCT) is very or somewhat effective in reducing lung cancer mortality in current smokers; LDCT was perceived as more effective than chest × ray or sputum cytology. Responding to vignettes describing asymptomatic patients of varying smoking exposure, 67% of PCPs recommended lung cancer screening for at least one of the vignettes. Most PCPs recommending screening said they would use chest × ray; up to 26% would use LDCT. In adjusted analyses, PCPs’ beliefs and practice style were strongly associated with their lung cancer screening recommendations.
Many PCPs’ lung cancer screening beliefs and recommendations are inconsistent with current evidence and guidelines. Provider education regarding lung cancer screening’s evidence base and guideline content is indicated.
PMCID: PMC3133954  PMID: 20965378
22.  Inhibition and Role of let-7d in Idiopathic Pulmonary Fibrosis 
Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation.
Objectives: To determine changes in expression and role of microRNAs in IPF.
Methods: RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-β. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry.
Measurements and Main Results: Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-β down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and α-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells.
Conclusions: Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis.
Clinical trial registered with (NCT 00258544).
PMCID: PMC2913236  PMID: 20395557
epithelial–mesenchymal transition; HMGA2 (high-mobility group AT-hook 2); microRNA; transforming growth factor-β
23.  Persistent Pneumocystis colonization leads to the development of chronic obstructive pulmonary disease (COPD) in a non-human primate model of AIDS 
The Journal of infectious diseases  2010;202(2):302-312.
HIV-infected patients are at increased risk for development of pulmonary complications, including chronic obstructive pulmonary disease (COPD). Inflammation associated with sub-clinical infection has been postulated to promote COPD. Persistence of Pneumocystis (Pc) is associated with HIV and COPD, although a causal relationship has not been established. We used a simian/human immunodeficiency virus (SHIV) model of HIV infection to study pulmonary effects of Pc colonization. SHIV-infected/Pc-colonized monkeys developed progressive obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Elevated Th2 cytokines and pro-inflammatory mediators in bronchoalveolar lavage fluid coincided with Pc colonization and pulmonary function decline. These results support the concept that an infectious agent contributes to development of HIV-associated lung disease and suggests that Pc colonization may be a risk factor for the development of HIV-associated COPD. Furthermore, this model allows examination of early host responses important to disease progression thus identifying potential therapeutic targets for COPD.
PMCID: PMC2946196  PMID: 20533880
Pneumocystis; COPD; SHIV; AIDS; HIV
24.  High Throughput Determination of TGFβ1/SMAD3 Targets in A549 Lung Epithelial Cells 
PLoS ONE  2011;6(5):e20319.
Transforming growth factor beta 1 (TGFβ1) plays a major role in many lung diseases including lung cancer, pulmonary hypertension, and pulmonary fibrosis. TGFβ1 activates a signal transduction cascade that results in the transcriptional regulation of genes in the nucleus, primarily through the DNA-binding transcription factor SMAD3. The objective of this study is to identify genome-wide scale map of SMAD3 binding targets and the molecular pathways and networks affected by the TGFβ1/SMAD3 signaling in lung epithelial cells.
We combined chromatin immunoprecipitation with human promoter region microarrays (ChIP-on-chip) along with gene expression microarrays to study global transcriptional regulation of the TGFβ1/SMAD3 pathway in human A549 alveolar epithelial cells. The molecular pathways and networks associated with TGFβ1/SMAD3 signaling were identified using computational approaches. Validation of selected target gene expression and direct binding of SMAD3 to promoters were performed by quantitative real time RT-PCR and electrophoretic mobility shift assay on A549 and human primary lung epithelial cells.
Results and Conclusions
Known TGFβ1 target genes such as SERPINE1, SMAD6, SMAD7, TGFB1 and LTBP3, were found in both ChIP-on-chip and gene expression analyses as well as some previously unrecognized targets such as FOXA2. SMAD3 binding of FOXA2 promoter and changed expression were confirmed. Computational approaches combining ChIP-on-chip and gene expression microarray revealed multiple target molecular pathways affected by the TGFβ1/SMAD3 signaling. Identification of global targets and molecular pathways and networks associated with TGFβ1/SMAD3 signaling allow for a better understanding of the mechanisms that determine epithelial cell phenotypes in fibrogenesis and carcinogenesis as does the discovery of the direct effect of TGFβ1 on FOXA2.
PMCID: PMC3098871  PMID: 21625455
25.  Contextual Analysis of Breast Cancer Stage at Diagnosis Among Women in the United States, 2004 
To explore contextual effects and to test for interactions, this study examined how breast cancer stage at diagnosis among U.S. women related to individual- and county-level (contextual) variables associated with access to health care and socioeconomic status.
Individual-level incidence data were obtained from the National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology and End-Results (SEER) program. The county of residence of women with diagnosed breast cancer (n = 217,299) was used to link NPCR and SEER data with county-level measures of health care access from the 2004 Area Resource File (ARF). In addition to individual-level covariates such as age, race, and Hispanic ethnicity, we examined county-level covariates (residence in a Health Professional Shortage Area, urban/rural residence; race/ethnicity; and number of health centers/clinics, mammography screening centers, primary care physicians, and obstetrician-gynecologists per 100,000 female population or per 1000 square miles) as predictors of stage of breast cancer at diagnosis.
Both individual-level and contextual variables are associated with later stage of breast cancer at diagnosis. Black women and women of “other race” had higher odds of receiving a diagnosis of regional or distant stage breast cancer (P <0.0001 and P = 0.02). With adjustment for age, Hispanics were more likely to receive a diagnosis of later stage breast cancer than non-Hispanics (P <0.0.001). Women living in areas with a higher proportion of black women had greater odds of receiving a diagnosis of regional or late stage breast cancer compared with women living in areas with the lowest proportion of black women. The same was noted for women living in areas with intermediate proportions of Hispanic women (age-adjusted odds ratio [OR], 0.94; 95% confidence interval [CI], 0.92–0.97]. Other important contextual variables associated with stage at diagnosis included the percentage of persons living below the poverty level and the number of office-based physicians per 100,000 women. Women living in counties with a higher proportion of persons living below the poverty level or fewer office-based physicians were more likely to receive a diagnosis of later stage breast cancer than those living in other counties (P < 0.001). In multivariable analysis, residence in areas with a higher proportion of non-Hispanic black women modified the associations of age and Hispanic ethnicity with later stage breast cancer (P = 0.0159 and P = 0.0002, respectively).
This study found that county-level contextual variables related to the availability and accessibility of health care providers and health services can affect the timeliness of breast cancer diagnosis. This information could help public health officials develop interventions to reduce the burden of breast cancer among U.S. women.
PMCID: PMC3039173  PMID: 21331349
Breast cancer; cancer prevention and control; screening; stage

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