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1.  A vascular transport operator 
The American journal of physiology  1993;265(6 0 2):H2196-H2208.
A pulse or a sharp front in concentration of a tracer or a substrate in the blood within a vessel becomes dispersed while being transported along a vessel. Cross-stream mixing and pulsations in flow with the heartbeat cause the dispersion to be less than would occur with a parabolic velocity profile (Newtonian flow). These characteristics allow intravascular mass transport to be described well by a simple two-parameter differential operator, which is a one-dimensional representation of the rather complex real situation. The operator consists of two components in series, a pure delay and a fourth-order linear differential operator. The latter is merely two underdamped second-order operators in series, with fixed relationships between the natural frequencies and damping coefficients. The operator is useful because it provides a transport function with skewness and kurtosis suitable to intravascular transport where the mean velocity profile is blunter than in Newtonian parabolic flow. The parameters of the operator are its mean transit time, t̄, and its relative dispersion, RD, which is the standard deviation of the response impulse divided by t̄. The operator transport function describes blood transport through the human leg arterial system, where the RD values are ~ 15-20%.
PMCID: PMC4169179  PMID: 8285259
vascular transport delay; velocity profile in blood; human femoral artery; dorsalis pedis artery; indocyanine green dye; indicator dilution
3.  Potassium and Thallium Uptake in Dog Myocardium 
We sought to ascertain the rates and mechanisms of uptake of markers for regional myocardial blood flows.
Methods
The rates of exchange of potassium and thallium across capillary walls and cell membranes in isolated blood-perfused dog hearts were estimated from multiple indicator dilution curves recorded for131I-albumin, 42K and 201Tl from the coronary sinus outflow following injection into arterial inflow. Analysis involved fitting the observed dilution curves with a model composed of a capillary-interstitial fluid-cell exchange region and nonexchanging larger vessels.
Results
Capillary permeability surface products (PSc) for potassium and thallium were similar, 0.82 ± 0.33 (mean ± s.d., n = 19) and 0.87 ± 0.32 ml min−1 g−1 (n = 24) with a ratio for simultaneous pairs of 1.02 ± 0.27 (n = 19). For the myocardial cells, PSpc averaged 3.7 ± 3.1 ml min−1 g−1 (n = 19) for K+ and 9.5 ± 3.9 (n = 24) for Tl+; the ratio of potassium to thallium averaged 0.40 ± 0.19 (n = 18), thereby omitting a single high value for potassium. This high cellular influx for thallium is interpreted as due to its passage through ionic channels for both Na+ and K+.
Conclusion
The high permeabilities and large volumes of distribution make thallium and potassium among the best ionic deposition markers for regional flow. Their utility for this purpose is compromised by significant capillary barrier limitation retarding uptake; so regional flow is underestimated modestly in high-flow regions particularly.
PMCID: PMC4031322  PMID: 9025754
capillary permeability; cation transport; myocardial imaging agents; regional myocardial blood flow
4.  The Role of a Radiology Electronic Notification System in the Emergency Department Setting and Its Impact on Patient Care 
Background
To determine the impact of a radiology electronic notification system (ENS) on emergency department (ED) patient care.
Materials and Methods
A retrospective review of de-identified patient data for a 2-year period (1 year prior to and 1 year following ENS implementation) was approved by the hospital’s institutional review board. The effect of a radiology ENS on ED patient care was investigated by analyzing the intervals between completion of a chest radiograph and the times antibiotics were ordered/administered on patients presenting with symptoms of community acquired pneumonia (CAP). The square root transformation of the means was analyzed with an ANOVA model to determine statistical significance.
Results
During the 24-month study protocol, 1,341 patients who were evaluated in the ED met the study eligibility criteria. The least square estimates of the mean times from when the chest radiograph was completed to when antibiotics were ordered prior to and after the implementation of the ENS were 89 and 107 minutes, respectively (P < 0.01). The least square estimates of the mean times from when the chest radiograph was completed to when antibiotics were administered prior to and after the implementation of the ENS were 115 and 132 minutes, respectively (P = 0.02).
Conclusion
The implementation of a radiology ENS does have advantages for the radiologist in streamlining the communication and documentation processes but may negatively impact time to treatment and thus patient care.
doi:10.14740/jocmr1821w
PMCID: PMC4039098  PMID: 24883152
Emergency department; Radiology electronic notification system; Patient care
5.  Growth in Percutaneous Coronary Intervention Capacity Relative to Population and Disease Prevalence 
Background
The access to and growth of percutaneous coronary intervention (PCI) has not been fully explored with regard to geographic equity and need. Economic factors and timely access to primary PCI provide the impetus for growth in PCI centers, and this is balanced by volume standards and the benefits of regionalized care.
Methods and Results
Geospatial and statistical analyses were used to model capacity, growth, and access of PCI hospitals relative to population density and myocardial infarction (MI) prevalence at the state level. Longitudinal data were obtained for 2003–2011 from the American Hospital Association, the U.S. Census, and the Centers for Disease Control and Prevention (CDC) with geographical modeling to map PCI locations. The number of PCI centers has grown 21.2% over the last 8 years, with 39% of all hospitals having interventional cardiology capabilities. During the same time, the US population has grown 8.3%, from 217 million to 235 million, and MI prevalence rates have decreased from 4.0% to 3.7%. The most densely concentrated states have a ratio of 8.1 to 12.1 PCI facilities per million of population with significant variability in both MI prevalence and average distance between PCI facilities.
Conclusions
Over the last decade, the growth rate for PCI centers is 1.5× that of the population growth, while MI prevalence is decreasing. This has created geographic imbalances and access barriers with excess PCI centers relative to need in some regions and inadequate access in others.
doi:10.1161/JAHA.113.000370
PMCID: PMC3886741  PMID: 24166491
acute coronary syndrome; cardiovascular disease prevalence; percutaneous coronary intervention
6.  Trauma Exposure and Posttraumatic Stress Disorder Among Employees of New York City Companies Affected by the September 11, 2001 Attacks on the World Trade Center 
Disaster medicine and public health preparedness  2011;5(0 2):10.1001/dmp.2011.50.
Objective
Several studies have provided prevalence estimates of posttraumatic stress disorder (PTSD) related to the September 11, 2001 (9/11) attacks in broadly affected populations, although without sufficiently addressing qualifying exposures required for assessing PTSD and estimating its prevalence. A premise that people throughout the New York City area were exposed to the attacks on the World Trade Center (WTC) towers and are thus at risk for developing PTSD has important implications for both prevalence estimates and service provision. This premise has not, however, been tested with respect to DSM-IV-TR criteria for PTSD. This study examined associations between geographic distance from the 9/11 attacks on the WTC and reported 9/11 trauma exposures, and the role of specific trauma exposures in the development of PTSD.
Methods
Approximately 3 years after the attacks, 379 surviving employees (102 with direct exposures, including 65 in the towers, and 277 with varied exposures) recruited from 8 affected organizations were interviewed using the Diagnostic Interview Schedule/Disaster Supplement and reassessed at 6 years. The estimated closest geographic distance from the WTC towers during the attacks and specific disaster exposures were compared with the development of 9/11–related PTSD as defined by the Diagnostic and Statistical Manual, Fourth Edition, Text Revision.
Results
The direct exposure zone was largely concentrated within a radius of 0.1 mi and completely contained within 0.75 mi of the towers. PTSD symptom criteria at any time after the disaster were met by 35% of people directly exposed to danger, 20% of those exposed only through witnessed experiences, and 35% of those exposed only through a close associate’s direct exposure. Outside these exposure groups, few possible sources of exposure were evident among the few who were symptomatic, most of whom had preexisting psychiatric illness.
Conclusions
Exposures deserve careful consideration among widely affected populations after large terrorist attacks when conducting clinical assessments, estimating the magnitude of population PTSD burdens, and projecting needs for specific mental health interventions.
doi:10.1001/dmp.2011.50
PMCID: PMC3842159  PMID: 21900416
September 11 attacks; posttraumatic stress disorder; trauma exposure; disaster; disaster mental health services
7.  Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling 
Bioorganic & medicinal chemistry  2012;20(18):5642-5648.
Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated antimelanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug.
doi:10.1016/j.bmc.2012.07.004
PMCID: PMC3495316  PMID: 22892214
Riluzole; Prodrug; Cancer; Melanoma; Cyp1A2
9.  Regionally Selective Atrophy after Traumatic Axonal Injury 
Archives of neurology  2010;67(11):1336-1344.
Objectives
To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.
Design
Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.
Setting
Inpatient traumatic brain injury unit
Patients or Other Participants
Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.
Main Outcome Measure
Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.
Results
Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.
Conclusion
Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.
doi:10.1001/archneurol.2010.149
PMCID: PMC3465162  PMID: 20625067
10.  Fractal Nature of Regional Myocardial Blood Flow Heterogeneity 
Circulation Research  1989;65(3):578-590.
Spatial variation in regional flows within the heart, skeletal muscle, and in other organs, and temporal variations in local arteriolar velocities and flows is measurable even with low resolution techniques. A problem in the assessment of the importance of such variations has been that the observed variance increases with increasing spatial or temporal resolution in the measurements. This resolution-dependent variance is now shown to be described by the fractal dimension, D. For example, the relative dispersion (RD=SD/mean) of the spatial distribution of flows for a given spatial resolution, is given by: RD(m)=RD(mref)·(mmref)1−Dg where m is the mass of the pieces of tissue in grams, and the reference level of dispersion, RD(mref), is taken arbitrarily to be the RD found using pieces of mass mref, which is chosen to be 1 g. Thus, the variation in regional flow within an organ can be described with two parameters, RD(mref) and the slope of the logarithmic relationship defined by the spatial fractal dimension Ds. In the heart, this relation has been found to hold over a wide range of piece sizes, the fractal Ds being about 1.2 and the correlation coefficient 0.99. A Ds of 1.2 suggests moderately strong correlation between local flows; a Ds=1.0 indicates uniform flow and a Ds= 1.5 indicates complete randomness.
PMCID: PMC3361973  PMID: 2766485
2-iododesmethylimipramine; microspheres; regional myocardial blood flow; flow heterogeneity; heart; fractals; relative dispersion coefficient of variation; sheep; baboons; rabbits
11.  A framework on surface-based connectivity quantification for the human brain 
Journal of neuroscience methods  2011;197(2):324-332.
Quantifying the connectivity between arbitrary surface patches in the human brain cortex can be used in studies on brain function and to characterize clinical diseases involving abnormal connectivity. Cortical regions of human brain in their natural forms can be represented in surface formats. In this paper, we present a framework to quantify connectivity using cortical surface segmentation and labeling from structural magnetic resonance images, tractography from diffusion tensor images, and nonlinear inter-subject registration. For a single subject, the connectivity intensity of any point on the cortical surface is set to unity if the point is connected and zero if it is not connected. The connectivity proportion is defined as the ratio of the total connected surface area to the total area of the surface patch. By nonlinearly registering the connectivity data of a group of normal controls into a template space, a population connectivity metric can be defined as either the average connectivity intensity of a cortical point or the average connectivity proportion of a cortical region. In the template space, a connectivity profile and a connectivity histogram of an arbitrary cortical region of interest can then be derived from these connectivity quantification values. Results from the application of these quantification metrics to a population of schizophrenia patients and normal controls are presented, revealing connectivity signatures of specified cortical regions and detecting connectivity abnormalities.
doi:10.1016/j.jneumeth.2011.02.017
PMCID: PMC3081907  PMID: 21396960
connectivity; quantification; DTI; cortical surface; tractography
12.  Modeling Blood Flow Heterogeneity 
Annals of biomedical engineering  1996;24(3):352-372.
It has been known for some time that regional blood flows within an organ are not uniform. Useful measures of heterogeneity of regional blood flows are the standard deviation and coefficient of variation or relative dispersion of the probability density function (PDF) of regional flows obtained from the regional concentrations of tracers that are deposited in proportion to blood flow. When a mathematical model is used to analyze dilution curves after tracer solute administration, for many solutes it is important to account for flow heterogeneity and the wide range of transit times through multiple pathways in parallel. Failure to do so leads to bias in the estimates of volumes of distribution and membrane conductances. Since in practice the number of paths used should be relatively small, the analysis is sensitive to the choice of the individual elements used to approximate the distribution of flows or transit times. Presented here is a method for modeling heterogeneous flow through an organ using a scheme that covers both the high flow and long transit time extremes of the flow distribution. With this method, numerical experiments are performed to determine the errors made in estimating parameters when flow heterogeneity is ignored, in both the absence and presence of noise. The magnitude of the errors in the estimates depends upon the system parameters, the amount of flow heterogeneity present, and whether the shape of the input function is known. In some cases, some parameters may be estimated to within 10% when heterogeneity is ignored (homogeneous model), but errors of 15–20% may result, even when the level of heterogeneity is modest. In repeated trials in the presence of 5% noise, the mean of the estimates was always closer to the true value with the heterogeneous model than when heterogeneity was ignored, but the distributions of the estimates from the homogeneous and heterogeneous models overlapped for some parameters when outflow dilution curves were analyzed. The separation between the distributions was further reduced when tissue content curves were analyzed. It is concluded that multipath models accounting for flow heterogeneity are a vehicle for assessing the effects of flow heterogeneity under the conditions applicable to specific laboratory protocols, that efforts should be made to assess the actual level of flow heterogeneity in the organ being studied, and that the errors in parameter estimates are generally smaller when the input function is known rather than estimated by deconvolution.
PMCID: PMC3212991  PMID: 8734057
Heterogeneity; Circulatory transport; Vascular dispersion; Capillary permeability–surface area products; Blood–tissue exchange kinetics; Indicator dilution
13.  Fractal Dimension Analysis of the Cortical Ribbon in Mild Alzheimer’s Disease 
NeuroImage  2010;53(2):471-479.
Fractal analysis methods are used to quantify the complexity of the human cerebral cortex. Many recent studies have focused on high resolution three-dimensional reconstructions of either the outer (pial) surface of the brain or the junction between the grey and white matter, but ignore the structure between these surfaces. This study uses a new method to incorporate the entire cortical thickness. Data were obtained from the Alzheimer’s Disease (AD) Neuroimaging Initiative database (Control N=35, Mild AD N=35). Image segmentation was performed using a semi-automated analysis program. The fractal dimensions of three cortical models (the pial surface, grey/white surface and entire cortical ribbon) were calculated using a custom cube-counting triangle-intersection algorithm. The fractal dimension of the cortical ribbon showed highly significant differences between control and AD subjects (p<0.001). The inner surface analysis also found smaller but significant differences (p< 0.05). The pial surface dimensionality was not significantly different between the two groups. All three models had a significant positive correlation with the cortical gyrification index (r > 0.55, p<0.001). Only the cortical ribbon had a significant correlation with cortical thickness (r = 0.832, p< 0.001) and the Alzheimer’s Disease Assessment Scale cognitive battery (r = −0.513, p = 0.002). The cortical ribbon dimensionality showed a larger effect size (d=1.12) in separating control and mild AD subjects than cortical thickness (d=1.01) or gyrification index (d=0.84). The methodological change shown in this paper may allow for further clinical application of cortical fractal dimension as a biomarker for structural changes that accrue with neurodegenerative diseases.
doi:10.1016/j.neuroimage.2010.06.050
PMCID: PMC2942777  PMID: 20600974
Fractal Dimension; Cortex; Complexity; Alzheimer’s disease; Cortical Thickness; Gyrification Index
14.  Etiology of Sudden Death in the Community: Results of Anatomic, Metabolic and Genetic Evaluation 
American heart journal  2010;159(1):33-39.
Background
Identifying persons at risk for sudden cardiac death (SCD) is challenging. A comprehensive evaluation may reveal clues about the clinical, anatomic, genetic and metabolic risk factors for SCD.
Methods
Seventy-one SCD victims (25–60 years-old) without an initially apparent cause of death were evaluated at the Hennepin County Medical Examiner’s office from August, 2001 to July, 2004. We reviewed their clinic records conducted next-of-kin interviews and performed autopsy, laboratory testing and genetic analysis for mutations in genes associated with the long-QT syndrome.
Results
Mean age was 49.5±7 years, 86% were male and 2 subjects had history of coronary heart disease (CHD). Coronary risk factors were highly prevalent in comparison to individuals of the same age group in this community (e.g. smoking 61%; hypertension 27%; hyperlipidemia 25%) but inadequately treated. On autopsy, 80% of the subjects had high-grade coronary stenoses. Acute coronary lesions and previous silent myocardial infarction (MI) were found in 27% and 34%, respectively. Further, 32% of the subjects had recently smoked cigarettes and 50% had ingested analgesics. Possible deleterious mutations of the ion channel genes were detected in 5 (7%) subjects. Of these, 4 were in the sodium channel gene SCN5A.
Conclusions
Overwhelming majority of the SCD victims in the community had severe subclinical CHD, including undetected previous MI. Traditional coronary risk factors were prevalent and under-treated. Mutations in the long-QT syndrome genes were detected in a few subjects. These findings imply that improvements in the detection and treatment of subclinical CHD in the community are needed to prevent SCD.
doi:10.1016/j.ahj.2009.10.019
PMCID: PMC2905235  PMID: 20102864
death; sudden; epidemiology; genetics; pathology; coronary disease
15.  Characterization of Atrophic Changes in the Cerebral Cortex Using Fractal Dimensional Analysis 
Brain imaging and behavior  2009;3(2):154-166.
The purpose of this project is to apply a modified fractal analysis technique to high-resolution T1 weighted magnetic resonance images in order to quantify the alterations in the shape of the cerebral cortex that occur in patients with Alzheimer’s disease. Images were selected from the Alzheimer’s Disease Neuroimaging Initiative database (Control N=15, Mild-Moderate AD N=15). The images were segmented using a semi-automated analysis program. Four coronal and three axial profiles of the cerebral cortical ribbon were created. The fractal dimensions (Df) of the cortical ribbons were then computed using a box-counting algorithm. The mean Df of the cortical ribbons from AD patients were lower than age-matched controls on six of seven profiles. The fractal measure has regional variability which reflects local differences in brain structure. Fractal dimension is complementary to volumetric measures and may assist in identifying disease state or disease progression.
doi:10.1007/s11682-008-9057-9
PMCID: PMC2927230  PMID: 20740072
Fractal dimension; Alzheimer’s disease; Neuroimaging initiative; Cerebral cortex; Fractal analysis
16.  Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement 
Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy–Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.
doi:10.1007/s10654-008-9302-y
PMCID: PMC2764094  PMID: 19189221
Gene–disease associations; Genetics; Gene–environment interaction; Systematic review; Meta analysis; Reporting recommendations; Epidemiology; Genome-wide association
17.  Intramedullary tibial nailing in distal third tibial fractures: distal locking screws and fracture non-union 
International Orthopaedics  2007;32(4):547-549.
Distal third tibial fractures are prone to non-union following tibial nail insertion. The purpose of this study was to assess the union of distal third tibial fractures in patients who have undergone intra-medullary (IM) tibial nailing with one versus two distal locking screws. Sixty-five patients who had intramedullary tibial nail fixation were retrospectively analysed. Our results showed that 80% of non-unions in distal third fractures had only one distal locking screw compared to 20% who had two distal locking screws. This is statistically significant (p<0.01). We therefore conclude that two distal locking screws are essential for distal third fractures.
doi:10.1007/s00264-007-0356-3
PMCID: PMC2532262  PMID: 17410364
18.  STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement 
PLoS Medicine  2009;6(2):e1000022.
Julian Little and colleagues present the STREGA recommendations, which are aimed at improving the reporting of genetic association studies.
doi:10.1371/journal.pmed.1000022
PMCID: PMC2634792  PMID: 19192942
gene-disease associations; genetics; gene-environment interaction; systematic review; meta analysis; reporting recommendations; epidemiology; genome-wide association
19.  Linkage Analysis of a Cluster-Based Quantitative Phenotype Constructed from Pulmonary Function Test Data in 27 Multigenerational Families with Multiple Asthmatic Members 
Human Heredity  2007;64(2):136-145.
Objective
To identify genes involved in phenotypes that increase one's risk for developing asthma, a complex disease that is likely genetically heterogeneous. Unlike other approaches to locus discovery in the presence of heterogeneity, this method seeks loci that segregate in all or most ascertained families while recognizing that other genes and environmental factors that modify the action of the common gene may vary across families.
Methods
The method is based on seeking groups of families that differ, between groups, in the way affected idndividuals express the genotype. Then we use the distance of each individual to the cluster center for his family to define a quantitative trait. This quantitative trait is then subjected to a genome scan using variance components methods.
Results
The method is applied to a data set of 27 multigenerational families with asthma, and a novel locus at 2q33 (at 210 cM) is identified.
Conclusions
The proposed method has the potential to identify loci near genes that increase risk for asthma related phenotypes. The method could be used for other complex disorders that exhibit locus heterogeneity.
doi:10.1159/000101992
PMCID: PMC2861531  PMID: 17476113
Asthma; Linkage analysis; Locus heterogeneity; Quantitative trait locus
20.  Novel Insights into Lung Transplant Rejection by Microarray Analysis 
Gene expression microarrays can estimate the prevalence of mRNA for thousands of genes in a small sample of cells or tissue. Organ transplant researchers are increasingly using microarrays to identify specific patterns of gene expression that predict and characterize acute and chronic rejection, and to improve our understanding of the mechanisms underlying organ allograft dysfunction. We used microarrays to assess gene expression in bronchoalveolar lavage cell samples from lung transplant recipients with and without acute rejection on simultaneous lung biopsies. These studies showed increased expression during acute rejection of genes involved in inflammation, apoptosis, and T-cell activation and proliferation. We also studied gene expression during the evolution of airway obliteration in a murine heterotopic tracheal transplant model of chronic rejection. These studies demonstrated specific patterns of gene expression at defined time points after transplantation in allografts, whereas gene expression in isografts reverted back to that of native tracheas within 2 wk after transplantation. These studies demonstrate the potential power of microarrays to identify biomarkers of acute and chronic lung rejection. The application of new genetic, genomic, and proteomic technologies is in its infancy, and the microarray-based studies described here are clearly only the beginning of their application to lung transplantation. The massive amount of data generated per tissue or cell sample has spawned an outpouring of invention in the bioinformatics field, which is developing methodologies to turn data into meaningful and reproducible clinical and mechanistic inferences.
doi:10.1513/pats.200605-110JG
PMCID: PMC2647614  PMID: 17202291
allograft rejection; lung transplantation; microarray
21.  Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus 
Arthritis Research  2001;3(5):299-305.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies to a wide range of self-antigens. Recent genome screens have implicated numerous chromosomal regions as potential SLE susceptibility loci. Among these, the 1q41 locus is of particular interest, because evidence for linkage has been found in several independent SLE family collections. Additionally, the 1q41 locus appears to be syntenic with a susceptibility interval identified in the NZM2410 mouse model for SLE. Here, we report the results of genotyping of 11 microsatellite markers within the 1q41 region in 210 SLE sibpair and 122 SLE trio families. These data confirm the modest evidence for linkage at 1q41 in our family collection (LOD = 1.21 at marker D1S2616). Evidence for significant linkage disequilibrium in this interval was also found. Multiple markers in the region exhibit transmission disequilibrium, with the peak single marker multiallelic linkage disequilibrium noted at D1S490 (pedigree disequilibrium test [PDT] global P value = 0.0091). Two- and three-marker haplotypes from the 1q41 region similarly showed strong transmission distortion in the collection of 332 SLE families. The finding of linkage together with significant transmission disequilibrium provides strong evidence for a susceptibility locus at 1q41 in human SLE.
PMCID: PMC64842  PMID: 11549371
1q41; autoimmunity; linkage; systemic lupus erythematosus; transmission disequilibrium
23.  Linkage Analysis between the Major Histocompatibility System and Insulin-dependent Diabetes in Families with Patients in Two Consecutive Generations 
Journal of Clinical Investigation  1980;65(3):592-601.
We have histocompatibility (HLA) genotyped 28 families with insulin-dependent diabetics in two or more consecutive generations, usually parent and child. This strategy of ascertainment was used to maximize the likelihood of obtaining a homogeneous type of disease within a family, and an autosomal dominant mode of inheritance. 76 diabetics and 169 nondiabetics were studied in these families.
The frequencies of the antigens Dw3 and Dw4, and the genotype Dw3/Dw4 among the diabetics are 59, 68, and 30%, respectively, as compared with 15, 12, and 2% in normal controls, and 43, 41, and 10% in the nondiabetic relatives of the diabetics. Dw2 is present in only one diabetic (4%), as compared with 18% in normal controls and 17% in nondiabetic relatives.
HLA haplotype concordance was analyzed for sib pairs in relation to the haplotype shared by the affected parent/child pair, and for the diabetic sib pairs within each sibship. The results failed to reveal deviations in the expected HLA haplotype assortment. Assuming an autosomal dominant mode and several penetrance levels, linkage analysis between the HLA and diabetes was performed. The total lod score is 0.37 for a recombination fraction of 0.29 at 50% penetrance. Although the linkage and concordance analysis results are inconclusive, they seem to be different from those reported by us for families with normal parents and two or more diabetic sibs. Because ascertainment biases may have influenced these results in an unquantifiable manner, it is not certain whether the two types of families are genetically different. However, the marked difference in the lod scores for the 50% penetrant autosomal recessive model between the two types of families is compatible with a genetic dissimilarity between them. The high frequency of the Dw3 and Dw4 antigens, the Dw3/Dw4 genotype, and the decreased frequency of Dw2, however, indicate the existence of two or more important diabetic genetic factors associated with the D region of the HLA in these families.
PMCID: PMC371400  PMID: 6766467
24.  The Histocompatibility System in Juvenile, Insulin-Dependent Diabetic Multiplex Kindreds 
Journal of Clinical Investigation  1977;60(5):989-998.
We have histocompatibility (HLA) genotyped 24 families with two or more juvenile, insulin-dependent, ketosis-prone diabetic siblings. This criterion for family selection was used to obtain a homogeneous form of diabetes within a sibship, because diabetes appears to be a genetically heterogeneous disease. 58 diabetic and 53 nondiabetic sibs and 40 parents were studied. 55% of the diabetic pairs were concordant for both HLA haplotypes (expected 25%), 40% were concordant for one haplotype (expected 50%), and 5% were discordant for both haplotypes (expected 25%). These values are significantly different from the expected values (P < 0.001). On the other hand, the inheritance of haplotypes among the nondiabetic sibs in these families was not significantly different from the expected mendelian segregation.
When comparing 20 pairs of HLA identical (sharing two haplotypes) with 15 pairs of haploidential (sharing one haplotype) diabetic sibs for the intrapair difference in age of onset of disease, we found that the HLA identical sibs were significantly more concordant for age of onset (3.9 yr difference) than the haploidential (7.3 yr difference) (P < 0.05). The same type of analysis for the difference in seasonal incidence in months revealed that the HLA indentical sibs were more concordant (1.8 mo difference) than the haploidentical sibs (3.2 mo difference) (P < 0.025). Furthermore, the HLA identical diabetic sibs were more likely to develop diabetes in the winter months (78%) than the haploidentical diabetic sibs (21%).
No particular HLA haplotype or antigen seemed to be associated with any particular clinical feature.
These data are compatible with the theory of genetic heterogeneity of juvenile, insulin-dependent diabetes. It is suggested that there are one or more diabetes response genes in the HLA region playing an important role in the pathogenesis of juvenile, insulin-dependent diabetes in the families studied here. It is, however, possible that other genes, not associated with the HLA complex, may play an etiologic role in some cases of juvenile, insulin-dependent diabetes, resulting in lack of association between HLA and some forms of diabetes.
PMCID: PMC372450  PMID: 908763
25.  STrengthening the REporting of Genetic Association studies (STREGA) – an extension of the STROBE statement 
Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy–Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct or analysis.
doi:10.1111/j.1365-2362.2009.02125.x
PMCID: PMC2730482  PMID: 19297801
Epidemiology; gene-disease associations; gene-environment interaction; genetics; genome-wide association; meta-analysis; reporting recommendations; systematic review

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