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1.  Percentile Ranking and Citation Impact of a Large Cohort of NHLBI-funded Cardiovascular R01 Grants 
Circulation research  2014;114(4):600-606.
Funding decisions for cardiovascular R01 grant applications at NHLBI largely hinge on percentile rankings. It is not known whether this approach enables the highest impact science.
To conduct an observational analysis of percentile rankings and bibliometric outcomes for a contemporary set of funded NHLBI cardiovascular R01 grants.
Methods and results
We identified 1492 investigator-initiated de novo R01 grant applications that were funded between 2001 and 2008, and followed their progress for linked publications and citations to those publications. Our co-primary endpoints were citations received per million dollars of funding, citations obtained within 2-years of publication, and 2-year citations for each grant’s maximally cited paper. In 7654 grant-years of funding that generated $3004 million of total NIH awards, the portfolio yielded 16,793 publications that appeared between 2001 and 2012 (median per grant 8, 25th and 75th percentiles 4 and 14, range 0 – 123), which received 2,224,255 citations (median per grant 1048, 25th and 75th percentiles 492 and 1,932, range 0 – 16,295). We found no association between percentile ranking and citation metrics; the absence of association persisted even after accounting for calendar time, grant duration, number of grants acknowledged per paper, number of authors per paper, early investigator status, human versus non-human focus, and institutional funding. An exploratory machine-learning analysis suggested that grants with the very best percentile rankings did yield more maximally cited papers.
In a large cohort of NHLBI-funded cardiovascular R01 grants, we were unable to find a monotonic association between better percentile ranking and higher scientific impact as assessed by citation metrics.
PMCID: PMC3959724  PMID: 24406983
Research funding; bibliometrics; scientific impact; NHLBI
2.  The association between cardiovascular risk and cardiovascular magnetic resonance measures of fibrosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Risk scores for cardiovascular disease (CVD) are in common use to integrate multiple cardiovascular risk factors in order to identify individuals at greatest risk for disease. The purpose of this study was to determine if individuals at greater cardiovascular risk have T1 mapping indices by cardiovascular magnetic resonance (CMR) indicative of greater myocardial fibrosis.
CVD risk scores for 1208 subjects (men, 50.8%) ages 55–94 years old were evaluated in the Multiethnic Study of Atherosclerosis (MESA) at six centers. T1 times were determined at 1.5Tesla before and after gadolinium administration (0.15 mmol/kg) using a modified Look-Locker pulse sequence. The relationship between CMR measures (native T1, 12 and 25 minute post-gadolinium T1, partition coefficient and extracellular volume fraction) and 14 established different cardiovascular risk scores were determined using regression analysis. Bootstrapping analysis with analysis of variance was used to compare different CMR measures. CVD risk scores were significantly different for men and women (p < 0.001).
25 minute post gadolinium T1 time showed more statistically significant associations with risk scores (10/14 scores, 71%) compared to other CMR indices (e.g. native T1 (7/14 scores, 50%) and partition coefficient (7/14, 50%) in men. Risk scores, particularly the new 2013 AHA/ASCVD risk score, did not correlate with any CMR fibrosis index.
Men with greater CVD risk had greater CMR indices of myocardial fibrosis. T1 times at greater delay time (25 minutes) showed better agreement with commonly used risk score indices compared to ECV and native T1 time.
Clinical trial registration, NCT00005487.
PMCID: PMC4326517
Myocardium; Cardiovascular magnetic resonance; Risk factors
4.  Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia 
Leukemia  2011;26(4):700-707.
In cell and animal models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, evidence involving short telomeres in cancer development in humans is scarce, epidemiologic, and indirect. Here we directly implicate telomere shortening as a critical molecular event for malignant evolution in aplastic anemia. Patients’ telomere lengths at diagnosis of aplastic anemia, while comparable to age-matched controls, inversely correlated with the probability of developing a cytogenetically abnormal clone. A significantly increased number of telomere signal-free chromosomal ends and chromosomal numerical and structural abnormalities were observed in bone marrow cells of patients with shorter telomeres in comparison to patients with longer telomeres and healthy subjects. The proportion of monosomy 7 cells in the bone marrow at diagnosis of aplastic anemia inversely correlated with telomere length, years before the emergence of an autonomous and clinically detectable abnormal clone. Marrow cells of clinically healthy individuals carrying loss-of-function telomerase mutations and with extremely short telomeres also showed chromosomal instability in vitro. These results provide the first clinical direct evidence in humans that short telomeres in hematopoietic cells are dysfunctional, mediate chromosomal instability, and predispose to malignant transformation in a human disease.
PMCID: PMC4169071  PMID: 22005790
telomere; chromosome instability; aplastic anemia; leukemia; myelodysplasia; cancer
5.  Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia 
British journal of haematology  2008;144(2):206-216.
Horse anti-thymocyte globulin (h-ATG) and cyclosporine are the initial therapy for most patients with severe aplastic anaemia (SAA), but there is no practical and reliable method to predict response to this treatment. To determine whether pre-treatment blood counts discriminate patients with SAA who have a higher likelihood of haematological response at 6 months to immunosuppressive therapy (IST), we conducted a single institution retrospective analysis on 316 SAA patients treated with h-ATG-based IST from 1989 to 2005. In multivariate analysis, younger age, higher baseline absolute reticulocyte count (ARC), and absolute lymphocyte count (ALC) were highly predictive of response at 6 months. Patients with baseline ARC ≥ 25 × 109 /l and ALC ≥ 1 × 109 /l had a much greater probability of response at 6 months following IST compared to those with lower ARC and ALC (83% vs. 41%, respectively; p < 0.001). This higher likelihood of response translated to greater rate of 5-year survival in patients in the high ARC/ALC group (92%) compared to those with a low ARC/ALC (53%). In the era of IST, the baseline ARC and ALC together serve as a simple predictor of response following IST, which should guide in risk stratification among patients with SAA.
PMCID: PMC4149225  PMID: 19036108
Aplastic anaemia; antibody therapy; bone marrow failure
6.  Prognostic value of myocardial circumferential strain for incident heart failure and cardiovascular events in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis 
European Heart Journal  2013;34(30):2354-2361.
Left ventricular (LV) circumferential strain (Ecc) is a sensitive index of regional myocardial function. Currently, no studies have assessed its prognostic value in general population. We sought to investigate whether Ecc has a prognostic value for predicting incident heart failure (HF) and other major cardiovascular events in asymptomatic individuals without a history of previous cardiovascular diseases.
Methods and results
We, prospectively, assessed incident HF and atherosclerotic events during a 5.5 ± 1.3-year period in 1768 asymptomatic individuals aged 45–84 (mean age 65 years; 47% female) who underwent tagged magnetic resonance imaging for strain determination. During the follow-up period, 39 (2.2%) participants experienced incident HF and 108 (6.1%) participants had atherosclerotic cardiovascular events. Average of peak Ecc of 12-LV segments (Ecc-global) and mid-slice (Ecc-mid) was −17.0 ± 2.4 and −17.5 ± 2.7%, respectively. Participants with average absolute Ecc-mid lower than −16.9% had a higher cumulative hazard of incident HF (log-rank test, P = 0.001). In cox regression analysis, Ecc-mid predicted incident HF independent of age, diabetes status, hypertension, interim myocardial infarction, LV mass index, and LV ejection fraction (hazard ratio 1.15 per 1%, 95% CI: 1.01–1.31, P = 0.03). This relationship remained significant after adjustment for LV-end-systolic wall stress into covariates. In addition, by adding Ecc-mid to risk factors, LV ejection fraction, and the LV mass index, both the global χ2 value (76.6 vs. 82.4, P = 0.04) and category-less net-reclassification index (P = 0.01, SE = 0.18, z = 2.53) were augmented for predicting HF. Circumferential strain was also significantly related to the composite atherosclerotic cardiovascular events, but its relationship was attenuated after introducing the LV mass index.
Circumferential shortening provides robust, independent, and incremental predictive value for incident HF in asymptomatic subjects without any history of previous clinical cardiovascular disease.
Clinical Trial Registration Unique identifier: NCT00005487.
PMCID: PMC3736058  PMID: 23644181
Myocardial function; Heart failure; Cardiovascular events
7.  N-terminal Pro-B-Type Natriuretic Peptide, Left Ventricular Mass, and Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2012;5(6):727-734.
Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population.
Methods and Results
A total of 5597 multi-ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5±1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54–2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3–10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001).
Plasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population.
Clinical Trial Registration
URL: Unique identifier: NCT00005487.
PMCID: PMC4124746  PMID: 23032197
N-terminal pro-B-type natriuretic peptide; heart failure; left ventricular mass
8.  Prognostic Implications of Left Ventricular Dyssynchrony for Major Adverse Cardiovascular Events in Asymptomatic Women and Men: The Multi‐Ethnic Study of Atherosclerosis 
Left ventricular (LV) dyssynchrony is related to adverse outcomes in systolic heart failure, but its prognostic importance in asymptomatic population is not known. Our objective was to assess the prognostic implications of LV mechanical dyssynchrony in a large multiethnic population before the occurrence of global LV dysfunction.
Methods and Results
A total of 1392 participants in the Multi‐Ethnic Study of Atherosclerosis (MESA; mean age: 64.7 years; 46% were women) with cardiac magnetic resonance imaging at baseline were followed for a median duration of 8.3 years. Harmonic phase imaging analysis was used to derive systolic circumferential strain. Greater standard deviation of time to peak systolic strain (SD‐TPS) indicates greater dyssynchrony. With SD‐TPS as a continuous variable, Cox proportional hazards analysis was used to assess hazards ratio after adjusting for demographics, cardiovascular risk factors, LV mass‐to‐volume ratio, and ejection fraction. Using the 75th percentile of SD‐TPS as a cutoff, Kaplan–Meier analysis was performed between 2 categorical groups for each gender. Higher values of dyssynchrony in women predicted major adverse cardiovascular events, defined as myocardial infarction, heart failure, stroke, and death (hazard ratio: 1.01 per 1‐ms increment in SD‐TPS, P=0.015), hard coronary events (hazard ratio: 1.05 per 1‐ms increment in SD‐TPS, P=0.026), and cerebrovascular events (hazard ratio: 1.03 per 1‐ms increment in SD‐TPS, P=0.013). In contrast, dyssynchrony in men was not predictive of events. Kaplan–Meier analyses in women revealed increased event occurrence in the higher dyssynchrony group, but this was not the case in men.
In an asymptomatic cohort, greater LV dyssynchrony determined by cardiac magnetic resonance imaging predicts adverse cardiovascular outcome in women but not in men.
Clinical Trial Registration
URL: Unique identifier: NCT00005487.
PMCID: PMC4310386  PMID: 25092789
cardiac magnetic resonance imaging; cardiovascular events; left ventricular dyssynchrony; prognosis
9.  Left Ventricular Global Function Index By Magnetic Resonance Imaging- A Novel Marker for Assessment of Cardiac Performance for the Prediction Of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(4):770-778.
LV function is generally assessed independent of structural remodeling and vice versa. The purpose of this study was to evaluate a novel LV global function index (LVGFI) that integrates LV structure with global function and to assess its predictive value for cardiovascular (CV) events throughout adult life in a multi-ethnic population of men and women without history of cardiovascular diseases at baseline. A total of 5004 participants in the Multi-Ethnic Study of Atherosclerosis underwent a cardiac magnetic resonance (CMR) study and were followed up for a median of 7.2 years. The LVGFI by CMR was defined by the ratio of stroke volume divided by LV total volume defined as the sum of mean LV cavity and myocardial volumes. Cox proportional hazard models were constructed to predict the end points of heart failure (HF), hard CV events and a combined endpoint of all CV events after adjustment for established risk factors, calcium score and biomarkers. A total of 579 (11.6%) incident events were observed during the follow-up period. In adjusted models, the end points of HF, hard CV events and all events were all significantly associated with LVGFI (HF, hazard ratio [HR]= 0.64, p<0.0001; hard CV events, HR=0.79, p=0.007; all events, HR=0.79, p<0.0001). LVGFI had a significant independent predictive value in the multivariable models for all CV event categories. The LVGFI was a powerful predictor of incident heart failure, hard CV events and a composite endpoint including all events in this multiethnic cohort.
PMCID: PMC3691067  PMID: 23424238
left ventricle; ejection fraction; heart failure; LV mass; LV global function index
10.  Long term outcome of pediatric patients with severe aplastic anemia treated with anti-thymocyte globulin and cyclosporine 
The Journal of pediatrics  2008;153(6):814-819.
To determine the long term outcomes in children with severe aplastic anemia (SAA) treated with anti-thymocyte globulin (ATG) and cyclosporine (CsA), we conducted a retrospective analysis of the pediatric patients treated at our institution in all protocols that included horse ATG + CsA.
Study design
From 1989 to 2006, 406 patients, of whom about 20% were children under the age of 18, received an initial course of immunosuppressive therapy (IST) at our institution. Here we report the outcome of 77 children who were treated with a horse ATG + CsA based regimen during this time.
The overall response rate at 6 months was 74% (57/77); the cumulative incidence of relapse at 10 years was 33%, and the median time to relapse was 558 days. The cumulative incidence of evolution following IST was 8.5%; all 3 such events occurred among partial responders. Overall, there were 13 deaths (17%): four occurred within the 3 months following IST in patients who had a pre-treatment ANC of less than 100/uL, and nine deaths occurred more than 6 months after initiating IST. The median time to death was 570 days. The overall 10-year survival for the entire cohort was 80%; long term survival in children who responded to IST was 89%.
The long term survival in pediatrics patients who respond to IST is excellent, at about 90%. IST remains a good alternative in pediatric patients who lack an HLA-matched sibling donor and should be offered as initial therapy, prior to an alternative HSCT.
PMCID: PMC3971527  PMID: 18672253
aplastic anemia; anti-thymocyte globulin; response; immunosuppression; pediatrics; survival
11.  Metabolic Syndrome, Strain, and Reduced Myocardial Function: Multi-Ethnic Study of Atherosclerosis 
Arquivos Brasileiros de Cardiologia  2014;102(4):327-335.
Subclinical cardiovascular disease is prevalent in patients with Metabolic Syndrome (MetSyn). Left ventricular (LV) circumferential strain (εCC) and longitudinal strain (εLL), assessed by Speckle Tracking Echocardiography (STE), are indices of systolic function: shortening is indicated by negative strain, and thus, the more negative the strain, the better the LV systolic function. They have been used to demonstrate subclinical ventricular dysfunction in several clinical disorders.
We hypothesized that MetSyn is associated with impaired myocardial function, as assessed by STE.
We analyzed Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent STE and were evaluated for all MetSyn components.
Among the 133 participants included [women: 63%; age: 65 ± 9 years (mean ± SD)], the prevalence of MetSyn was 31% (41/133). Individuals with MetSyn had lower εCC and lower εLL than those without MetSyn (-16.3% ± 3.5% vs. -18.4% ± 3.7%, p < 0.01; and -12.1% ± 2.5% vs. -13.9% ± 2.3%, p < 0.01, respectively). The LV ejection fraction (LVEF) was similar in both groups (p = 0.09). In multivariate analysis, MetSyn was associated with less circumferential myocardial shortening as indicated by less negative εCC (B = 2.1%, 95%CI:0.6 3.5, p < 0.01) even after adjusting for age, ethnicity, LV mass, and LVEF). Likewise, presence of MetSyn (B = 1.3%, 95%CI:0.3 2.2, p < 0.01) and LV mass (B = 0.02%, 95% CI: 0.01-0.03, p = 0.02) were significantly associated with less longitudinal myocardial shortening as indicated by less negative εLL after adjustment for ethnicity, LVEF, and creatinine.
Left ventricular εCC and εLL, markers of subclinical cardiovascular disease, are impaired in asymptomatic individuals with MetSyn and no history of myocardial infarction, heart failure, and/or LVEF < 50%.
PMCID: PMC4028951  PMID: 24844874
Atherosclerosis; Metabolic X Syndrome; Diabetes Mellitus / mortality; Ventricular Dysfunction / physiopathology; Ethnic Group
12.  Impact on Modes of Inheritance and Relative Risks of using Extreme Sampling When Designing Genetic Association Studies 
Annals of human genetics  2012;77(1):80-84.
Using extreme phenotypes for association studies can improve statistical power. We study the impact of using samples with extremely high or low traits on the alternative model space, the genotype relative risks, and the genetic models in association studies. We prove the following results: when the risk allele causes high trait values, the more extreme the high traits, the larger the genotype relative risks, which is not always true for using extreme low traits; we also prove that a genetic model theoretically changes with more extreme trait except for the recessive or dominant models. Practically, however, the impact of deviations from the true genetic model at a functional locus due to selective sampling is virtually negligible. The implications of our findings are discussed. Numerical values are reported for illustrations.
PMCID: PMC3535545  PMID: 23163532
Association studies; Extreme sampling; Genetic models; Genotype relative risks; Replication
13.  Age, Gender and Hypertension-Related Remodeling Influences Left Ventricular Torsion Assessed by Tagged Cardiac Magnetic Resonance in Asymptomatic Individuals: The Multi-Ethnic Study of Atherosclerosis 
Circulation  2012;126(21):2481-2490.
The aim of the present study was to evaluate how torsion is influenced by left ventricular (LV) remodeling associated with age, gender and hypertension in a large community-based population.
Methods and Results
Myocardial shortening and torsion were assessed by tagged cardiac magnetic resonance (CMR) in 1478 participants without clinically apparent cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA). Torsion was defined as the difference between apical and basal rotation, divided by slice distance. In multivariable linear regression models, older age was associated with lower stroke volume (−3.6 ml/decade, p<0.001) and higher LV mass –to-volume ratio (0.03 g/ml/decade, p<0.001) along with lower circumferential shortening (−0.17%/decade, p<0.05). Torsion, however, was greater at older ages (0.14 °/decade, p<0.001) and in women (0.37°/cm vs. men, p<0.001). Hypertensive participants had higher LV mass and LV mass –to-volume ratio (15.5g and 0.07 g/ml, respectively, p<0.001 for both). Circumferential shortening was lower in hypertensive (−0.42%, p<0.01), whereas torsion was higher after adjustment for age and gender (0.17°/cm, p<0.05).
Older age is associated with lower LV volumes and greater relative wall thickness, and accompanied by lower circumferential myocardial shortening, whereas torsion is greater with older age. Hypertensive individuals have greater LV volumes and relative wall thickness and lower circumferential shortening. Torsion, however, is greater in hypertension independent of age and gender. Torsion may therefore represent a compensatory mechanism to maintain an adequate stroke volume and cardiac output in the face of progressively reduced LV volumes and myocardial shortening associated with hypertension and aging.
PMCID: PMC3558706  PMID: 23147172
Torsion; Hypertension; Age; remodeling; Cardiac Magnetic Resonance
14.  Donor KIR Genes 2DL5A, 2DS1 and 3DS1 Are Associated with a Reduced Rate of Leukemia Relapse After HLA-Identical Sibling Stem Cell Transplantation for Acute Myeloid Leukemia but Not Other Hematologic Malignancies 
Stem cell transplantation (SCT) from a healthy donor can be curative for patients with hematologic malignancies resistant to other treatments. Elimination of malignant cells through a graft-versus-leukemia (GVL) effect involves donor T and natural killer (NK) cells, but their relative contribution to this process is poorly defined. NK cell alloreactivity and GVL effects are controlled by the nature of the interaction of NK activation receptors and killer-immunoglobulin-like-receptors (KIR) with major histocompatibility locus class I antigens on the target cell. We performed KIR-genotyping of HLA-identical sibling donors in 246 T cell-depleted SCTs to identify genetic factors affecting transplant outcome (treatment-related mortality [TRM], leukemic relapse, and survival). Univariate and multivariate analysis of transplant-related risk factors and KIR genotyping was performed to identify independent variables predictive of outcome for different forms of leukemia. Further to confirming known predictive factors for TRM and survival (CD34 cell dose, patient age, disease stage), statistical analysis revealed that 3 donor B haplotype KIR genes, 2DL5A, 2DSI, and 3DSI, were associated with significantly less relapse in patients with acute myelogenous leukemia (AML) (13% versus 57%) but not in patients with other myelogenous or lymphoid malignancies. AML patients receiving SCT from donors with these KIR genes relapsed 4 times less frequently than patients transplanted from donors with other KIR genotypes. These findings suggest specific, genetically determined, interactions between NK cells and AML cells that facilitate the GVL effect, and have implications for donor selection for AML patients.
PMCID: PMC3801172  PMID: 20302958
NK cells; Stem cell transplantation; Activatory KIR; Relapse; Acute myelogenous leukemia
15.  High Sensitivity C-Reactive Protein as an Independent Predictor of Progressive Myocardial Functional Deterioration: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2012;164(2):251-258.
Systemic inflammation has been linked to the development of heart failure in population studies including MESA (Multi-Ethnic Study of Atherosclerosis) but little evidence exists regarding potential mechanism of this relationship. In this study, we used longitudinal MRI follow-up analysis to examine whether C-reactive protein (CRP) levels relate to progressive myocardial functional deterioration as a potential mechanism of incident heart failure.
Regional myocardial functional data from MESA participants who had baseline CRP measurement and also underwent tagged cardiac MRI both at baseline and at five-year follow-up were analyzed. Left ventricular (LV) midwall and mid-slice peak circumferential strain (Ecc), of which a more negative value denotes stronger regional myocardial function, was measured. Ecc change was calculated as the difference between baseline and follow-up Ecc.
During the follow-up period, participants (n=785) with elevated CRP experienced a decrease in strain, independent of age, gender and ethnicity (B=0.081; ΔEcc change per 1mg/L CRP change, 95% CI 0.036–0.126, p<0.001, Model 1), and additionally beyond systolic blood pressure, heart rate, diabetes, smoking status, body mass index, current medication and glomerular filtration rate (B=0.099, 0.052–0.145, p<0.001, Model 2). The relationship remained statistically significant after further adjustment for LV mass, coronary calcium score and interim clinical coronary events (B=0.098, 0.049–0.147, p<0.001, Model 3).
Higher CRP levels are related to progressive myocardial functional deterioration independent of subclinical atherosclerosis and clinical coronary events in asymptomatic individuals without previous history of heart disease.
PMCID: PMC3417227  PMID: 22877812
inflammation; myocardial function; magnetic resonance imaging
16.  Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia 
Critically short telomeres produce apoptosis, cell senescence and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia (SAA) but their clinical significance is unknown.
To investigate the relationship between telomere length and clinical outcomes in SAA.
Design and Setting
Single institution analysis of SAA patients treated in sequential prospective protocols at NIH from 2000 to 2008.
We retrospectively analyzed pre-treatment leukocyte age-adjusted telomere length in 183 patients with SAA consecutively enrolled into immunosuppression protocols with anti-thymocyte globulin plus cyclosporine for correlation with clinical outcomes.
Main Outcomes Measures
The outcomes studied were hematologic response, relapse, clonal evolution and survival.
There was no relationship between hematologic response and telomere length with response rates of 56.5%, 54.3%, 60%, and 56.5% in the first (n=46), second (n=46), third (n=45), and fourth quartiles (n=46), respectively. In multivariate analysis, telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (HR=0.16; 95% CI, 0.03–0.69; p=0.01). The rate of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7%–37.5%) compared to quartiles 2–4 (8.4%; 95% CI, 3.2%–13.3%; p=0.009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%–31.6%) compared to quartiles 2–4 (4.5%; 95% CI, 0.5%–8.2%; p=0.002). Survival between these two groups differed, with 66% (95% CI, 52.9%–82.5%) surviving 6 years in the first quartile compared to 83.8% (95% CI, 77.3%–90.9%) in quartiles 2–4 (p=0.008).
In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response, but was associated with risk of relapse, clonal evolution, and overall survival.
PMCID: PMC3721502  PMID: 20858879
The New England journal of medicine  2011;365(5):430-438.
In severe acquired aplastic anemia, hematopoietic failure is the result of immune mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine is an effective alternative to stem cell transplantation and improves blood counts and survival. While horse ATG is standard, rabbit ATG is more potent at depleting peripheral blood lymphocytes and is preferred in other clinical circumstances.
From December 2005 to July 2010, we performed a randomized trial comparing these two different ATG formulations at conventional regimens. Patients were treated at a single government facility. Primary outcome was hematologic response at 6 months, as determined by blood counts. The study was designed to accrue 60 patients per arm and powered to detect a 25% difference in response rate.
There was a large, unexpected difference in hematologic responses at 6 months in favor of horse ATG (68%; 95% confidence interval (CI), 56%–80%) compared to rabbit ATG (37%; 95% CI, 24%–49%; p<0.001). Overall survival at 3 years also differed, with 96% (95% CI, 90%–100%) surviving in the horse ATG group compared to 76% (95% CI, 61%–95%; p=0.04) in the rabbit ATG group when stem cell transplantation was censored, and 94% (95% CI, 88%–100%) for horse ATG and 70% (95% CI, 56%–86%; p=0.008) for rabbit ATG when stem cell transplantation events were not censored.
In a randomized study, rabbit ATG was markedly inferior to horse ATG as first treatment in severe aplastic anemia as measured by hematologic response and survival.
PMCID: PMC3721503  PMID: 21812672
18.  Inter-study reproducibility of cardiovascular magnetic resonance tagging 
The aim of this study is to determine the test-retest reliability of the measurement of regional myocardial function by cardiovascular magnetic resonance (CMR) tagging using spatial modulation of magnetization.
Twenty-five participants underwent CMR tagging twice over 12 ± 7 days. To assess the role of slice orientation on strain measurement, two healthy volunteers had a first exam, followed by image acquisition repeated with slices rotated ±15 degrees out of true short axis, followed by a second exam in the true short axis plane. To assess the role of slice location, two healthy volunteers had whole heart tagging. The harmonic phase (HARP) method was used to analyze the tagged images. Peak midwall circumferential strain (Ecc), radial strain (Err), Lambda 1, Lambda 2, and Angle α were determined in basal, mid and apical slices. LV torsion, systolic and early diastolic circumferential strain and torsion rates were also determined.
LV Ecc and torsion had excellent intra-, interobserver, and inter-study intra-class correlation coefficients (ICC range, 0.7 to 0.9). Err, Lambda 1, Lambda 2 and angle had excellent intra- and interobserver ICC than inter-study ICC. Angle had least inter-study reproducibility. Torsion rates had superior intra-, interobserver, and inter-study reproducibility to strain rates. The measurements of LV Ecc were comparable in all three slices with different short axis orientations (standard deviation of mean Ecc was 0.09, 0.18 and 0.16 at basal, mid and apical slices, respectively). The mean difference in LV Ecc between slices was more pronounced in most of the basal slices compared to the rest of the heart.
Intraobserver and interobserver reproducibility of all strain and torsion parameters was excellent. Inter-study reproducibility of CMR tagging by SPAMM varied between different parameters as described in the results above and was superior for Ecc and LV torsion. The variation in LV Ecc measurement due to altered slice orientation is negligible compared to the variation due to slice location.
Trial registration
This trial is registered as NCT00005487 at National Heart, Lung and Blood institute.
PMCID: PMC3667053  PMID: 23663535
CMR tagging; HARP; Test-retest reproducibility; SPAMM; Circumferential strain; Radial strain; Principal strains; Torsion
23.  Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia 
Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells.
We conducted a phase 2 study involving patients with aplastic anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag.
Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes.
Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia. (Funded by the National Heart, Lung, and Blood Institute; number, NCT00922883.)
PMCID: PMC3422737  PMID: 22762314
24.  Age-Related Changes in Aortic Arch Geometry: Relationship with Proximal Aortic Function and Left Ventricular Mass and Remodeling 
To define age-related geometric changes of the aortic arch and determine their relationship to central aortic stiffness and left ventricular remodeling.
The proximal aorta has been shown to thicken, enlarge in diameter and lengthen with aging in humans. However, no systematic study has described age-related longitudinal and transversal remodeling of the aortic arch and their relationship with left ventricular mass and remodeling.
We studied 100 subjects (55 women, 45 men, average age: 46±16 years) free of overt cardiovascular disease using magnetic resonance imaging to determine aortic arch geometry (length, diameters, height, width and curvature), aortic arch function (local aortic distensibility and arch pulse wave velocity PWV) and left ventricular volumes and mass. Radial tonometry was used to calculate central blood pressure.
Aortic diameters and arch length increased significantly with age. The ascending aorta increased most with age leading to aortic arch widening and decreased curvature. These geometric changes of the aortic arch were significantly related to decreased ascending aortic distensibility, increased aortic arch PWV (p<0.001) and to increased central blood pressures (p<0.001). Increased ascending aortic diameter, lengthening and decreased curvature of the aortic arch (unfolding) were all significantly associated with increased LV mass and concentric remodeling independently of age, gender, body size and central blood pressure (p<0.01).
Age-related unfolding of the aortic arch is related to increased proximal aortic stiffness in individuals without cardiovascular disease and associated with increased LV mass and mass-to-volume ratio independent of age, body size, central pressure and cardiovascular risk factors.
PMCID: PMC3508703  PMID: 21903061
magnetic resonance imaging; aortic geometry; aging; elasticity; left ventricular remodeling
25.  A shared parameter model for the estimation of longitudinal concomitant intervention effects 
Biostatistics (Oxford, England)  2011;12(4):737-749.
We investigate a change-point approach for modeling and estimating the regression effects caused by a concomitant intervention in a longitudinal study. Since a concomitant intervention is often introduced when a patient's health status exhibits undesirable trends, statistical models without properly incorporating the intervention and its starting time may lead to biased estimates of the intervention effects. We propose a shared parameter change-point model to evaluate the pre- and postintervention time trends of the response and develop a likelihood-based method for estimating the intervention effects and other parameters. Application and statistical properties of our method are demonstrated through a longitudinal clinical trial in depression and heart disease and a simulation study.
PMCID: PMC3202304  PMID: 21262930
Change-point model; Concomitant intervention; Likelihood; Longitudinal study; Shared parameter model

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