Publications by authors named "Andrea S Foulkes"

56 Publications

Body composition predictors of outcome in patients with COVID-19.

Int J Obes (Lond) 2021 Jul 9. Epub 2021 Jul 9.

Division of Musculoskeletal Imaging and Intervention, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Yawkey 6E, 55 Fruit Street, Boston, MA, USA.

Background/objective: Obesity is a strong risk factor for adverse outcomes in patients hospitalized with COVID-19, however, the distribution of fat and the amount of muscle mass are more accurate risk factors than BMI. The objective of this study was to assess body composition measures obtained on opportunistic abdominal CTs as predictors of outcome in patients hospitalized with COVID-19. We hypothesized that elevated visceral and intermuscular adipose tissue would be associated with adverse outcome.

Subjects/methods: Our retrospective study was IRB-approved and HIPAA-compliant. The study group comprised 124 patients (median age: 68 years, IQR: 56, 77; 59 weeks, 65 months) who were admitted with COVID-19 to a single hospital and who had undergone abdominal CT for clinical purposes. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and paraspinal and abdominal muscle cross-sectional areas (CSA) were assessed. Clinical information including prognostic factors, time of admission to the intensive care unit (ICU) and time of death within 28 days were obtained. Multivariate time-to-event competing risk models were fitted to estimate the hazard ratio (HR) for a composite outcome of ICU admission/mortality associated with a one standard deviation increase in each body compositional measure. Each model was adjusted for age, sex, race, BMI, and cardiometabolic comorbidities.

Results: There were 50 patients who were admitted to the ICU or deceased over a median time of 1 day [IQR 1, 6] from hospital admission. Higher VAT/SAT ratio (HR of 1.30; 95% CI 1.04-1.62, p = 0.022) and higher IMAT CSA (HR of 1.44; 95% CI 1.10-1.89, p = 0.008) were associated with a reduced time to ICU admission or death in adjusted models.

Conclusion: VAT/SAT and IMAT are predictors of adverse outcome in patients hospitalized with COVID-19, independent of other established prognostic factors. This suggests that body composition measures may serve as novel biomarkers of outcome in patients with COVID-19.
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http://dx.doi.org/10.1038/s41366-021-00907-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267764PMC
July 2021

Sex differences in inflammatory markers in patients hospitalized with COVID-19 infection: Insights from the MGH COVID-19 patient registry.

PLoS One 2021 28;16(4):e0250774. Epub 2021 Apr 28.

From the Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States of America.

Background: Men are at higher risk for serious complications related to COVID-19 infection than women. More robust immune activation in women has been proposed to contribute to decreased disease severity, although systemic inflammation has been associated with worse outcomes in COVID-19 infection. Whether systemic inflammation contributes to sex differences in COVID-19 infection is not known.

Study Design And Methods: We examined sex differences in inflammatory markers among 453 men (mean age 61) and 328 women (mean age 62) hospitalized with COVID-19 infection at the Massachusetts General Hospital from March 8 to April 27, 2020. Multivariable linear regression models were used to examine the association of sex with initial and peak inflammatory markers. Exploratory analyses examined the association of sex and inflammatory markers with 28-day clinical outcomes using multivariable logistic regression.

Results: Initial and peak CRP were higher in men compared with women after adjustment for baseline differences (initial CRP: ß 0.29, SE 0.07, p = 0.0001; peak CRP: ß 0.31, SE 0.07, p<0.0001) with similar findings for IL-6, PCT, and ferritin (p<0.05 for all). Men had greater than 1.5-greater odds of dying compared with women (OR 1.71, 95% CI 1.04-2.80, p = 0.03). Sex modified the association of peak CRP with both death and ICU admission, with stronger associations observed in men compared with women (death: OR 9.19, 95% CI 4.29-19.7, p <0.0001 in men vs OR 2.81, 95% CI 1.52-5.18, p = 0.009 in women, Pinteraction = 0.02).

Conclusions: In a sample of 781 men and women hospitalized with COVID-19 infection, men exhibited more robust inflammatory activation as evidenced by higher initial and peak inflammatory markers, as well as worse clinical outcomes. Better understanding of sex differences in immune responses to COVID-19 infection may shed light on the pathophysiology of COVID-19 infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250774PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081177PMC
May 2021

Rationale and design of a large population study to validate software for the assessment of atrial fibrillation from data acquired by a consumer tracker or smartwatch: The Fitbit heart study.

Am Heart J 2021 Aug 15;238:16-26. Epub 2021 Apr 15.

Harvard Medical School, Boston, MA; Biostatistics Center, Massachusetts General Hospital, Boston, MA.

Background: Early detection of atrial fibrillation or flutter (AF) may enable prevention of downstream morbidity. Consumer wrist-worn wearable technology is capable of detecting AF by identifying irregular pulse waveforms using photoplethysmography (PPG). The validity of PPG-based software algorithms for AF detection requires prospective assessment.

Methods: The Fitbit Heart Study (NCT04380415) is a single-arm remote clinical trial examining the validity of a novel PPG-based software algorithm for detecting AF. The proprietary Fitbit algorithm examines pulse waveform intervals during analyzable periods in which participants are sufficiently stationary. Fitbit consumers with compatible wrist-worn trackers or smartwatches were invited to participate. Enrollment began May 6, 2020 and as of October 1, 2020, 455,699 participants enrolled. Participants in whom an irregular heart rhythm was detected were invited to attend a telehealth visit and eligible participants were then mailed a one-week single lead electrocardiographic (ECG) patch monitor. The primary study objective is to assess the positive predictive value of an irregular heart rhythm detection for AF during the ECG patch monitor period. Additional objectives will examine the validity of irregular pulse tachograms during subsequent heart rhythm detections, self-reported AF diagnoses and treatments, and relations between irregular heart rhythm detections and AF episode duration and time spent in AF.

Conclusions: The Fitbit Heart Study is a large-scale remote clinical trial comprising a unique software algorithm for detection of AF. The study results will provide critical insights into the use of consumer wearable technology for AF detection, and for characterizing the nature of AF episodes detected using consumer-based PPG technology.
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http://dx.doi.org/10.1016/j.ahj.2021.04.003DOI Listing
August 2021

Statins Are Associated with Improved 28-day Mortality in Patients Hospitalized with SARS-CoV-2 Infection.

medRxiv 2021 Apr 6. Epub 2021 Apr 6.

Background: Statins may be protective in viral infection and have been proposed as treatment in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

Objective: We evaluated the effect of statins on mortality in four groups hospitalized with (SARS-CoV-2) infection (continued statin, newly initiated statin, discontinued statin, never on statin).

Design: In a single center cohort study of 1179 patients hospitalized with SARS-CoV-2 infection, the outcome of death, Intensive Care Unit (ICU) admission or hospital discharge was evaluated. Patients' statin use, laboratory data, and co-morbidities were determined via chart review and electronic health records. Using marginal structural models to account for timing of statin initiation and competing risks, we compared the likelihood of severe outcomes in the four statin exposure groups.

Setting: Academic medical center in the United States.

Participants: Patients hospitalized with SARS-CoV-2 infection.

Measurements: 28-day mortality, ICU admission, or discharge.

Results: Among 1179 patients, 360 were never on a statin, 311 were newly initiated on a statin, 466 were continued on a statin, and 42 had a statin discontinued. In this cohort, 154 (13.1%) patients died by 28-days. With marginal structural model analysis, statin use reduced the hazard of 28-day mortality (HR 0.566 [CI 0.372, 0.862], p = 0.008). Both new initiation of statins (HR 0.493 [CI 0.253, 0.963], p=0.038) and continuing statin therapy reduced the hazard of 28-day mortality (HR 0.270 [CI 0.114, 0.637], p=0.003). Sensitivity analysis found that statin use was associated with improved mortality for patients > 65 years, but not for patients 65 years or younger.

Limitation: Observational design.

Conclusion: Statin therapy during hospitalization for SARS-CoV-2 infection, including new initiation and continuation of therapy, was associated with reduced short-term mortality.
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http://dx.doi.org/10.1101/2021.03.27.21254373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043489PMC
April 2021

Ascending arousal network connectivity during recovery from traumatic coma.

Neuroimage Clin 2020 19;28:102503. Epub 2020 Nov 19.

Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.

Background: It is not currently possible to predict which patients will develop chronic disorders of consciousness (DoC) after severe traumatic brain injury (TBI). Although the ascending arousal network (AAN) supports human consciousness, it is unknown which AAN pathways must be preserved for patients to recover consciousness.

Methods: Sixteen patients with acute traumatic coma and 16 matched healthy controls were scanned with high angular resolution diffusion imaging (HARDI). All patients recovered consciousness (Recovery Cohort). Nine were scanned longitudinally: first in the ICU (Acute), then at ≥5 months post-injury (Follow-up). Six separate patients with post-traumatic DoC were scanned ≥5 months post-injury (Chronic DoC Cohort). For each AAN pathway, we computed the median relative change in Acute-to-Follow-up Connectivity Probability (CP) in the Recovery Cohort. We then used Wilcoxon tests with Bonferroni correction to compare CP in each AAN pathway in the Recovery Cohort at Follow-up versus the Chronic DoC Cohort. In an exploratory analysis, we used principal component analysis (PCA) to determine whether linear combinations of AAN CP values could separate the Chronic DoC Cohort from the Recovery Cohort and the healthy controls.

Results: In the Recovery Cohort, the largest relative AAN CP changes were in the brainstem-to-thalamus (median [IQR] = 0.7 [0.09, 0.9]) and forebrain-to-occipital lobe (-0.8 [-0.9, -0.8]) pathways. The AAN connections that differed in the cross-sectional analysis between the Recovery Cohort at Follow-up and the Chronic DoC Cohort included brainstem-to-hypothalamus (W = 53, P = 0.02), brainstem-to-temporal lobe (W = 52, P = 0.04), and thalamus-to-temporal lobe (W = 54, P = 0.009). Plotting the first two principal components of AAN connectivity resulted in a linear separation of Chronic DoC patients from other study groups.

Conclusions: We provide evidence for a longitudinal increase in brainstem-thalamic connectivity during recovery of consciousness after traumatic coma. Cross-sectional analyses revealed that brainstem-hypothalamus, brainstem-temporal lobe, and thalamus-temporal lobe connectivity differed between patients who recovered consciousness and those with a chronic DoC. These observations provide the basis for further investigation into AAN connectivity as a biomarker for recovery of consciousness after traumatic coma.
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http://dx.doi.org/10.1016/j.nicl.2020.102503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724378PMC
June 2021

The role of obesity in inflammatory markers in COVID-19 patients.

Obes Res Clin Pract 2021 Jan-Feb;15(1):96-99. Epub 2020 Dec 23.

The Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States; Division of Cardiology, Massachusetts General Hospital, Boston, MA, United States. Electronic address:

Obesity has emerged as a significant risk factor for severe COVID-19 worldwide. Given both COVID-19 infection and obesity have been associated with increased systemic inflammation, we evaluated inflammatory markers in obese and non-obese individuals hospitalized for COVID-19 at Massachusetts General Hospital. We hypothesized that obese patients would have a more exuberant inflammatory response as evidenced by higher initial and peak inflammatory markers along with worse clinical outcomes. Of the 781 patients, 349 were obese (45%). Obese individuals had higher initial and peak levels of CRP and ESR as well as higher peak d-dimer (P < 0.01 for all) in comparison to non-obese individuals, while. IL-6 and ferritin were similar. In addition, obese individuals had a higher odds of requiring vasopressor use (OR 1.54, 95% CI 1.00-2.38, P = 0.05), developing hypoxemic respiratory failure (OR 1.58, 95% CI 1.04-2.40, P = 0.03) and death (OR 2.20, 95% CI 1.31-3.70, P = 0.003) within 28 days of presentation to care. Finally, higher baseline levels of CRP and D-dimer were associated with worse clinical outcomes even after adjustment for BMI. Our findings suggest greater disease severity in obese individuals is characterized by more exuberant inflammation.
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http://dx.doi.org/10.1016/j.orcp.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833898PMC
February 2021

Massachusetts general hospital Covid-19 registry reveals two distinct populations of hospitalized patients by race and ethnicity.

PLoS One 2020 22;15(12):e0244270. Epub 2020 Dec 22.

Harvard Medical School, Boston, Massachusetts, United States of America.

Objective: To evaluate differences by race/ethnicity in clinical characteristics and outcomes among hospitalized patients with Covid-19 at Massachusetts General Hospital (MGH).

Methods: The MGH Covid-19 Registry includes confirmed SARS-CoV-2-infected patients hospitalized at MGH and is based on manual chart reviews and data extraction from electronic health records (EHRs). We evaluated differences between White/Non-Hispanic and Hispanic patients in demographics, complications and 14-day outcomes among the N = 866 patients hospitalized with Covid-19 from March 11, 2020-May 4, 2020.

Results: Overall, 43% of patients hospitalized with Covid-19 were women, median age was 60.4 [IQR = (48.2, 75)], 11.3% were Black/non-Hispanic and 35.2% were Hispanic. Hispanic patients, representing 35.2% of patients, were younger than White/non-Hispanic patients [median age 51y; IQR = (40.6, 61.6) versus 72y; (58.0, 81.7) (p<0.001)]. Hispanic patients were symptomatic longer before presenting to care (median 5 vs 3d, p = 0.039) but were more likely to be sent home with self-quarantine than be admitted to hospital (29% vs 16%, p<0.001). Hispanic patients had fewer comorbidities yet comparable rates of ICU or death (34% vs 36%). Nonetheless, a greater proportion of Hispanic patients recovered by 14 days after presentation (62% vs 45%, p<0.001; OR = 1.99, p = 0.011 in multivariable adjusted model) and fewer died (2% versus 18%, p<0.001).

Conclusions: Hospitalized Hispanic patients were younger and had fewer comorbidities compared to White/non-Hispanic patients; despite comparable rates of ICU care or death, a greater proportion recovered. These results have implications for public health policy and the design and conduct of clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244270PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755195PMC
January 2021

Nonconserved Long Intergenic Noncoding RNAs Associate With Complex Cardiometabolic Disease Traits.

Arterioscler Thromb Vasc Biol 2021 01 12;41(1):501-511. Epub 2020 Nov 12.

Cardiology Division, Department of Medicine (M.E.O., E.C., H.L., C.X., M.P.R.), Columbia University, New York, NY.

Objective: Transcriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33-GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT (Genetic Investigation of Anthropometric Traits), UK Biobank, GLGC (Global Lipids Genetics Consortium), Cardiogram (Coronary Artery Disease Genome Wide Replication and Meta-Analysis), and DIAGRAM (Diabetes Genetics Replication and Meta-Analysis)/DIAMANTE (Diabetes Meta-Analysis of Trans-Ethnic Association Studies). These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study-associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation.

Conclusions: These findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.
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http://dx.doi.org/10.1161/ATVBAHA.120.315045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886007PMC
January 2021

COVID-19 severity in hospitalized patients with asthma: A matched cohort study.

J Allergy Clin Immunol Pract 2021 01 22;9(1):497-500. Epub 2020 Oct 22.

Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Mass; Clinical Epidemiology Program, Mongan Institute, Department of Medicine, Massachusetts General Hospital, Boston, Mass; Harvard Medical School, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaip.2020.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580590PMC
January 2021

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

N Engl J Med 2020 12 21;383(24):2333-2344. Epub 2020 Oct 21.

From Massachusetts General Hospital (J.H.S., M.J.F., N.J.S.-B., A.D.F., L.H., A.S.F., N.K.H., B.C.H., C.A.S., M.D., C.M.N., Y.-D.H., T.K.T., Z.D., A.S., R.S.W., A.Y.K., S.S., P.S., T.G.N., C.A.P., S.H.U., D.S.C., M.A.M., J.M.Y., K.A.B., E.M., A.Z., Z.D.D., M.B.B., M.K., K.M.D., J.D., M.M.L., M.K.M.), Brigham and Women's Hospital (A.E.W., S.N., B.N.W.), and Boston Medical Center (N.L., M.S.), Boston, North Shore Medical Center, Salem (R.S., A.M.B., C.C.), Newton-Wellesley Hospital, Newton (H.S., D.S.H.), Beth Israel Lahey Health, Burlington (M.A., M.D.P.), and St. Elizabeth's Medical Center, Brighton (J.F.) - all in Massachusetts.

Background: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear.

Methods: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses.

Results: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo.

Conclusions: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).
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http://dx.doi.org/10.1056/NEJMoa2028836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646626PMC
December 2020

Bayesian variable selection for high dimensional predictors and self-reported outcomes.

BMC Med Inform Decis Mak 2020 09 7;20(1):212. Epub 2020 Sep 7.

Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA, USA.

Background: The onset of silent diseases such as type 2 diabetes is often registered through self-report in large prospective cohorts. Self-reported outcomes are cost-effective; however, they are subject to error. Diagnosis of silent events may also occur through the use of imperfect laboratory-based diagnostic tests. In this paper, we describe an approach for variable selection in high dimensional datasets for settings in which the outcome is observed with error.

Methods: We adapt the spike and slab Bayesian Variable Selection approach in the context of error-prone, self-reported outcomes. The performance of the proposed approach is studied through simulation studies. An illustrative application is included using data from the Women's Health Initiative SNP Health Association Resource, which includes extensive genotypic (>900,000 SNPs) and phenotypic data on 9,873 African American and Hispanic American women.

Results: Simulation studies show improved sensitivity of our proposed method when compared to a naive approach that ignores error in the self-reported outcomes. Application of the proposed method resulted in discovery of several single nucleotide polymorphisms (SNPs) that are associated with risk of type 2 diabetes in a dataset of 9,873 African American and Hispanic participants in the Women's Health Initiative. There was little overlap among the top ranking SNPs associated with type 2 diabetes risk between the racial groups, adding support to previous observations in the literature of disease associated genetic loci that are often not generalizable across race/ethnicity populations. The adapted Bayesian variable selection algorithm is implemented in R. The source code for the simulations are available in the Supplement.

Conclusions: Variable selection accuracy is reduced when the outcome is ascertained by error-prone self-reports. For this setting, our proposed algorithm has improved variable selection performance when compared to approaches that neglect to account for the error-prone nature of self-reports.
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http://dx.doi.org/10.1186/s12911-020-01223-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487595PMC
September 2020

Diabetes as a Risk Factor for Poor Early Outcomes in Patients Hospitalized With COVID-19.

Diabetes Care 2020 12 26;43(12):2938-2944. Epub 2020 Aug 26.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA.

Objective: Diabetes and obesity are highly prevalent among hospitalized patients with coronavirus disease 2019 (COVID-19), but little is known about their contributions to early COVID-19 outcomes. We tested the hypothesis that diabetes is a risk factor for poor early outcomes, after adjustment for obesity, among a cohort of patients hospitalized with COVID-19.

Research Design And Methods: We used data from the Massachusetts General Hospital (MGH) COVID-19 Data Registry of patients hospitalized with COVID-19 between 11 March 2020 and 30 April 2020. Primary outcomes were admission to the intensive care unit (ICU), need for mechanical ventilation, and death within 14 days of presentation to care. Logistic regression models were adjusted for demographic characteristics, obesity, and relevant comorbidities.

Results: Among 450 patients, 178 (39.6%) had diabetes-mostly type 2 diabetes. Among patients with diabetes versus patients without diabetes, a higher proportion was admitted to the ICU (42.1% vs. 29.8%, respectively, = 0.007), required mechanical ventilation (37.1% vs. 23.2%, = 0.001), and died (15.9% vs. 7.9%, = 0.009). In multivariable logistic regression models, diabetes was associated with greater odds of ICU admission (odds ratio 1.59 [95% CI 1.01-2.52]), mechanical ventilation (1.97 [1.21-3.20]), and death (2.02 [1.01-4.03]) at 14 days. Obesity was associated with greater odds of ICU admission (2.16 [1.20-3.88]) and mechanical ventilation (2.13 [1.14-4.00]) but not with death.

Conclusions: Among hospitalized patients with COVID-19, diabetes was associated with poor early outcomes, after adjustment for obesity. These findings can help inform patient-centered care decision making for people with diabetes at risk for COVID-19.
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http://dx.doi.org/10.2337/dc20-1506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770271PMC
December 2020

Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit.

Neurocrit Care 2020 10 13;33(2):364-375. Epub 2020 Aug 13.

Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.
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http://dx.doi.org/10.1007/s12028-020-01062-7DOI Listing
October 2020

Stochastic imputation for integrated transcriptome association analysis of a longitudinally measured trait.

Stat Methods Med Res 2020 04 7;29(4):1167-1180. Epub 2019 Jun 7.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, MA, USA.

The mechanistic pathways linking genetic polymorphisms and complex disease traits remain largely uncharacterized. At the same time, expansive new transcriptome data resources offer unprecedented opportunity to unravel the mechanistic underpinnings of complex disease associations. Two-stage strategies involving conditioning on a single, penalized regression imputation for transcriptome association analysis have been described for cross-sectional traits. In this manuscript, we propose an alternative two-stage approach based on stochastic regression imputation that additionally incorporates error in the predictive model. Application of a bootstrap procedure offers flexibility when a closed form predictive distribution is not available. The two-stage strategy is also generalized to longitudinally measured traits, using a linear mixed effects modeling framework and a composite test statistic to evaluate whether the genetic component of gene-level expression modifies the biomarker trajectory over time. Simulations studies are performed to evaluate relative performance with respect to type-1 error rates, coverage, estimation error, and power under a range of conditions. A case study is presented to investigate the association between whole blood expression for each of five inflammasome genes with inflammatory response over time after endotoxin challenge.
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http://dx.doi.org/10.1177/0962280219852720DOI Listing
April 2020

A likelihood-based approach to transcriptome association analysis.

Stat Med 2019 04 4;38(8):1357-1373. Epub 2018 Dec 4.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, Massachusetts.

Elucidating the mechanistic underpinnings of genetic associations with complex traits requires formally characterizing and testing associated cell and tissue-specific expression profiles. New opportunities exist to bolster this investigation with the growing numbers of large publicly available omics level data resources. Herein, we describe a fully likelihood-based strategy to leveraging external resources in the setting that expression profiles are partially or fully unobserved in a genetic association study. A general framework is presented to accommodate multiple data types, and strategies for implementation using existing software packages are described. The method is applied to an investigation of the genetics of evoked inflammatory response in cardiovascular disease research. Simulation studies suggest appropriate type-1 error control and power gains compared to single regression imputation, the most commonly applied practice in this setting.
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http://dx.doi.org/10.1002/sim.8040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907891PMC
April 2019

Deep RNA Sequencing Uncovers a Repertoire of Human Macrophage Long Intergenic Noncoding RNAs Modulated by Macrophage Activation and Associated With Cardiometabolic Diseases.

J Am Heart Assoc 2017 Nov 13;6(11). Epub 2017 Nov 13.

Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY

Background: Sustained and dysfunctional macrophage activation promotes inflammatory cardiometabolic disorders, but the role of long intergenic noncoding RNA (lincRNA) in human macrophage activation and cardiometabolic disorders is poorly defined. Through transcriptomics, bioinformatics, and selective functional studies, we sought to elucidate the lincRNA landscape of human macrophages.

Methods And Results: We used deep RNA sequencing to assemble the lincRNA transcriptome of human monocyte-derived macrophages at rest and following stimulation with lipopolysaccharide and IFN-γ (interferon γ) for M1 activation and IL-4 (interleukin 4) for M2 activation. Through de novo assembly, we identified 2766 macrophage lincRNAs, including 861 that were previously unannotated. The majority (≈85%) was nonsyntenic or was syntenic but not annotated as expressed in mouse. Many macrophage lincRNAs demonstrated tissue-enriched transcription patterns (21.5%) and enhancer-like chromatin signatures (60.9%). Macrophage activation, particularly to the M1 phenotype, markedly altered the lincRNA expression profiles, revealing 96 lincRNAs differentially expressed, suggesting potential roles in regulating macrophage inflammatory functions. A subset of lincRNAs overlapped genomewide association study loci for cardiometabolic disorders. MacORIS (macrophage-enriched obesity-associated lincRNA serving as a repressor of IFN-γ signaling), a macrophage-enriched lincRNA not expressed in mouse macrophages, harbors variants associated with central obesity. Knockdown of MacORIS which is located in the cytoplasm, enhanced IFN-γ-induced JAK2 (Janus kinase 2) and STAT1 (signal transducer and activator of transcription 1) phosphorylation in THP-1 macrophages, suggesting a potential role as a repressor of IFN-γ signaling. Induced pluripotent stem cell-derived macrophages recapitulated the lincRNA transcriptome of human monocyte-derived macrophages and provided a high-fidelity model with which to study lincRNAs in human macrophage biology, particularly those not conserved in mouse.

Conclusions: High-resolution transcriptomics identified lincRNAs that form part of the coordinated response during macrophage activation, including specific macrophage lincRNAs associated with human cardiometabolic disorders that modulate macrophage inflammatory functions.
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http://dx.doi.org/10.1161/JAHA.117.007431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721798PMC
November 2017

A score test for genetic class-level association with nonlinear biomarker trajectories.

Stat Med 2017 Aug 23;36(19):3075-3091. Epub 2017 May 23.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, MA, U.S.A.

Emerging data suggest that the genetic regulation of the biological response to inflammatory stress may be fundamentally different to the genetic underpinning of the homeostatic control (resting state) of the same biological measures. In this paper, we interrogate this hypothesis using a single-SNP score test and a novel class-level testing strategy to characterize protein-coding gene and regulatory element-level associations with longitudinal biomarker trajectories in response to stimulus. Using the proposed class-level association score statistic for longitudinal data, which accounts for correlations induced by linkage disequilibrium, the genetic underpinnings of evoked dynamic changes in repeatedly measured biomarkers are investigated. The proposed method is applied to data on two biomarkers arising from the Genetics of Evoked Responses to Niacin and Endotoxemia study, a National Institutes of Health-sponsored investigation of the genomics of inflammatory and metabolic responses during low-grade endotoxemia. Our results suggest that the genetic basis of evoked inflammatory response is different than the genetic contributors to resting state, and several potentially novel loci are identified. A simulation study demonstrates appropriate control of type-1 error rates, relative computational efficiency, and power. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.7314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002775PMC
August 2017

Bayesian variable selection for post-analytic interrogation of susceptibility loci.

Biometrics 2017 06 17;73(2):603-614. Epub 2016 Nov 17.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, Massachusetts, U.S.A.

Understanding the complex interplay among protein coding genes and regulatory elements requires rigorous interrogation with analytic tools designed for discerning the relative contributions of overlapping genomic regions. To this aim, we offer a novel application of Bayesian variable selection (BVS) for classifying genomic class level associations using existing large meta-analysis summary level resources. This approach is applied using the expectation maximization variable selection (EMVS) algorithm to typed and imputed SNPs across 502 protein coding genes (PCGs) and 220 long intergenic non-coding RNAs (lncRNAs) that overlap 45 known loci for coronary artery disease (CAD) using publicly available Global Lipids Gentics Consortium (GLGC) (Teslovich et al., 2010; Willer et al., 2013) meta-analysis summary statistics for low-density lipoprotein cholesterol (LDL-C). The analysis reveals 33 PCGs and three lncRNAs across 11 loci with >50% posterior probabilities for inclusion in an additive model of association. The findings are consistent with previous reports, while providing some new insight into the architecture of LDL-cholesterol to be investigated further. As genomic taxonomies continue to evolve, additional classes such as enhancer elements and splicing regions, can easily be layered into the proposed analysis framework. Moreover, application of this approach to alternative publicly available meta-analysis resources, or more generally as a post-analytic strategy to further interrogate regions that are identified through single point analysis, is straightforward. All coding examples are implemented in R version 3.2.1 and provided as supplemental material.
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http://dx.doi.org/10.1111/biom.12620DOI Listing
June 2017

Genome-wide interrogation reveals hundreds of long intergenic noncoding RNAs that associate with cardiometabolic traits.

Hum Mol Genet 2016 07 10;25(14):3125-3141. Epub 2016 Jun 10.

Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA

Long intergenic noncoding RNAs (lincRNAs) play important roles in disease, but the vast majority of these transcripts remain uncharacterized. We defined a set of 54 944 human lincRNAs by drawing on four publicly available lincRNA datasets, and annotated ∼2.5 million single nucleotide polymorphisms (SNPs) from each of 15 cardiometabolic genome-wide association study datasets into these lincRNAs. We identified hundreds of lincRNAs with at least one trait-associated SNP: 898 SNPs in 343 unique lincRNAs at 5% false discovery rate, and 469 SNPs in 146 unique lincRNAs meeting Bonferroni-corrected P < 0.05. An additional 64 trait-associated lincRNAs were identified using a class-level testing strategy at Bonferroni-corrected P < 0.05. To better understand the genomic context and prioritize trait-associated lincRNAs, we examined the pattern of linkage disequilibrium between SNPs in the lincRNAs and SNPs that met genome-wide-significance in the region (±500 kb of lincRNAs). A subset of the lincRNA-trait association findings was replicated in independent Genome-wide association studies data from the Pakistan Risk of Myocardial Infarction Study study. For trait-associated lincRNAs, we also investigated synteny and conservation relative to mouse, expression patterns in five cardiometabolic-relevant tissues, and allele-specific expression in RNA sequencing data for adipose tissue and leukocytes. Finally, we revealed a functional role in human adipocytes for linc-NFE2L3-1, which is expressed in adipose and is associated with waist-hip ratio adjusted for BMI. This comprehensive profile of trait-associated lincRNAs provides novel insights into disease mechanism and serves as a launching point for interrogation of the biology of specific lincRNAs in cardiometabolic disease.
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http://dx.doi.org/10.1093/hmg/ddw154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181595PMC
July 2016

Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing.

Arterioscler Thromb Vasc Biol 2016 07 26;36(7):1434-47. Epub 2016 May 26.

From the Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine (J.L.), Department of Biostatistics and Epidemiology (Y.H., M.L.), Department of Genetics, Perelman School of Medicine (B.C., K.M., D.J.R.), and Cardiovascular Institute, Department of Medicine, Perelman School of Medicine (M.G., W.L., K.M.), University of Pennsylvania, Philadelphia; Irving Institute for Clinical and Translational Research (M.P.R.) and Division of Cardiology, Department of Medicine (C.X., H.Z., M.P.R.), Columbia University Medical Center, New York, NY; and Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, MA (S.N., A.S.F.).

Objective: Human macrophages can shift phenotype across the inflammatory M1 and reparative M2 spectrum in response to environmental challenges, but the mechanisms promoting inflammatory and cardiometabolic disease-associated M1 phenotypes remain incompletely understood. Alternative splicing (AS) is emerging as an important regulator of cellular function, yet its role in macrophage activation is largely unknown. We investigated the extent to which AS occurs in M1 activation within the cardiometabolic disease context and validated a functional genomic cell model for studying human macrophage-related AS events.

Approach And Results: From deep RNA-sequencing of resting, M1, and M2 primary human monocyte-derived macrophages, we found 3860 differentially expressed genes in M1 activation and detected 233 M1-induced AS events; the majority of AS events were cell- and M1-specific with enrichment for pathways relevant to macrophage inflammation. Using genetic variant data for 10 cardiometabolic traits, we identified 28 trait-associated variants within the genomic loci of 21 alternatively spliced genes and 15 variants within 7 differentially expressed regulatory splicing factors in M1 activation. Knockdown of 1 such splicing factor, CELF1, in primary human macrophages led to increased inflammatory response to M1 stimulation, demonstrating CELF1's potential modulation of the M1 phenotype. Finally, we demonstrated that an induced pluripotent stem cell-derived macrophage system recapitulates M1-associated AS events and provides a high-fidelity macrophage AS model.

Conclusions: AS plays a role in defining macrophage phenotype in a cell- and stimulus-specific fashion. Alternatively spliced genes and splicing factors with trait-associated variants may reveal novel pathways and targets in cardiometabolic diseases.
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http://dx.doi.org/10.1161/ATVBAHA.116.307573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919157PMC
July 2016

A Simple Test of Class-Level Genetic Association Can Reveal Novel Cardiometabolic Trait Loci.

PLoS One 2016 9;11(2):e0148218. Epub 2016 Feb 9.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, MA, United States of America.

Background: Characterizing the genetic determinants of complex diseases can be further augmented by incorporating knowledge of underlying structure or classifications of the genome, such as newly developed mappings of protein-coding genes, epigenetic marks, enhancer elements and non-coding RNAs.

Methods: We apply a simple class-level testing framework, termed Genetic Class Association Testing (GenCAT), to identify protein-coding gene association with 14 cardiometabolic (CMD) related traits across 6 publicly available genome wide association (GWA) meta-analysis data resources. GenCAT uses SNP-level meta-analysis test statistics across all SNPs within a class of elements, as well as the size of the class and its unique correlation structure, to determine if the class is statistically meaningful. The novelty of findings is evaluated through investigation of regional signals. A subset of findings are validated using recently updated, larger meta-analysis resources. A simulation study is presented to characterize overall performance with respect to power, control of family-wise error and computational efficiency. All analysis is performed using the GenCAT package, R version 3.2.1.

Results: We demonstrate that class-level testing complements the common first stage minP approach that involves individual SNP-level testing followed by post-hoc ascribing of statistically significant SNPs to genes and loci. GenCAT suggests 54 protein-coding genes at 41 distinct loci for the 13 CMD traits investigated in the discovery analysis, that are beyond the discoveries of minP alone. An additional application to biological pathways demonstrates flexibility in defining genetic classes.

Conclusions: We conclude that it would be prudent to include class-level testing as standard practice in GWA analysis. GenCAT, for example, can be used as a simple, complementary and efficient strategy for class-level testing that leverages existing data resources, requires only summary level data in the form of test statistics, and adds significant value with respect to its potential for identifying multiple novel and clinically relevant trait associations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747495PMC
July 2016

A guide to genome-wide association analysis and post-analytic interrogation.

Stat Med 2015 Dec 6;34(28):3769-92. Epub 2015 Sep 6.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, MA, U.S.A.

This tutorial is a learning resource that outlines the basic process and provides specific software tools for implementing a complete genome-wide association analysis. Approaches to post-analytic visualization and interrogation of potentially novel findings are also presented. Applications are illustrated using the free and open-source R statistical computing and graphics software environment, Bioconductor software for bioinformatics and the UCSC Genome Browser. Complete genome-wide association data on 1401 individuals across 861,473 typed single nucleotide polymorphisms from the PennCATH study of coronary artery disease are used for illustration. All data and code, as well as additional instructional resources, are publicly available through the Open Resources in Statistical Genomics project: http://www.stat-gen.org.
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http://dx.doi.org/10.1002/sim.6605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019244PMC
December 2015

Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2015 Aug 17;66(2):266-73. Epub 2015 Mar 17.

Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. Electronic address:

Background: Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD.

Study Design: Cross-sectional and longitudinal observational analysis.

Setting & Participants: Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Predictor: Quartiles of plasma CX3CL1 levels at baseline.

Outcomes: Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality.

Results: Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04).

Limitations: Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect.

Conclusions: Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.
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http://dx.doi.org/10.1053/j.ajkd.2015.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516570PMC
August 2015

Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study.

Eur Heart J 2014 Aug 4;35(31):2115-22. Epub 2013 Dec 4.

Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

Aims: Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown.

Methods And Results: We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13-1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio.

Conclusions: In CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.
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http://dx.doi.org/10.1093/eurheartj/eht481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132636PMC
August 2014

Serial cervicovaginal exposures with replication-deficient SIVsm induce higher dendritic cell (pDC) and CD4+ T-cell infiltrates not associated with prevention but a more severe SIVmac251 infection of rhesus macaques.

J Acquir Immune Defic Syndr 2014 Apr;65(4):405-13

*Department of Immunology, The Wistar Institute, Philadelphia, PA; †Caribbean Primate Research Center and Animal Resources Center, University of Puerto Rico (UPR), San Juan, PR; ‡University of Minnesota Medical School, Minneapolis, MN; §Division of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA; ‖Tulane National Primate Research Center, Covington, LA; Departments of ¶Microbiology and #Internal Medicine, UPR Medical School, San Juan, PR; and **School of Biological Sciences and ††Nebraska Center for Virology, University of Nebraska, Lincoln, NE.

Objective: Intravaginal exposure to simian immunodeficiency virus (SIV) acutely recruits interferon-alpha (IFN-α) producing plasmacytoid dendritic cells (pDC) and CD4 T-lymphocyte targets to the endocervix of nonhuman primates. We tested the impact of repeated cervicovaginal exposures to noninfectious, defective SIV particles over 72 hours on a subsequent cervicovaginal challenge with replication competent SIV.

Methods: Thirty-four female Indian Rhesus macaques were given a 3-day twice-daily vaginal exposures to either SIVsmB7, a replication-deficient derivative of SIVsmH3 produced by a T lymphoblast CEMx174 cell clone (n = 16), or to CEM supernatant controls (n = 18). On the fourth day, animals were either euthanized to assess cervicovaginal immune cell infiltration or intravaginally challenged with SIVmac251. Challenged animals were tracked for plasma viral load and CD4 counts and euthanized at 42 days after infection.

Results: At the time of challenge, macaques exposed to SIVsmB7, had higher levels of cervical CD123 pDCs (P = 0.032) and CD4 T cells (P = 0.036) than those exposed to CEM control. Vaginal tissues showed a significant increase in CD4 T-cell infiltrates (P = 0.048) and a trend toward increased CD68 cellular infiltrates. After challenge, 12 SIVsmB7-treated macaques showed 2.5-fold greater daily rate of CD4 decline (P = 0.0408), and viral load rise (P = 0.0036) as compared with 12 control animals.

Conclusions: Repeated nonproductive exposure to viral particles within a short daily time frame did not protect against infection despite pDC recruitment, resulting instead in an accelerated CD4 T-cell loss with an increased rate of viral replication.
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http://dx.doi.org/10.1097/QAI.0000000000000047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943721PMC
April 2014

Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).

J Am Coll Cardiol 2013 Aug 30;62(9):789-98. Epub 2013 May 30.

Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Objectives: This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).

Background: CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.

Methods: We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885).

Results: Of 268 SNPs reaching p < 5 × 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC.

Conclusions: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
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http://dx.doi.org/10.1016/j.jacc.2013.01.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953823PMC
August 2013

Mixed modeling of meta-analysis P-values (MixMAP) suggests multiple novel gene loci for low density lipoprotein cholesterol.

PLoS One 2013 6;8(2):e54812. Epub 2013 Feb 6.

Division of Biostatistics, School of Public Health and Health Sciences at the University of Massachusetts, Amherst, MA, USA.

Informing missing heritability for complex disease will likely require leveraging information across multiple SNPs within a gene region simultaneously to characterize gene and locus-level contributions to disease phenotypes. To this aim, we introduce a novel strategy, termed Mixed modeling of Meta-Analysis P-values (MixMAP), that draws on a principled statistical modeling framework and the vast array of summary data now available from genetic association studies, to test formally for locus level association. The primary inputs to this approach are: (a) single SNP level p-values for tests of association; and (b) the mapping of SNPs to genomic regions. The output of MixMAP is comprised of locus level estimates and tests of association. In application of MixMAP to summary data from the Global Lipids Gene Consortium, we suggest twelve new loci (PKN, FN1, UGT1A1, PPARG, DMDGH, PPARD, CDK6, VPS13B, GAD2, GAB2, APOH and NPC1) for low-density lipoprotein cholesterol (LDL-C), a causal risk factor for cardiovascular disease and we also demonstrate the potential utility of MixMAP in small data settings. Overall, MixMAP offers novel and complementary information as compared to SNP-based analysis approaches and is straightforward to implement with existing open-source statistical software tools.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054812PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566142PMC
December 2013

Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration.

J Infect Dis 2013 Jan 26;207(2):213-22. Epub 2012 Oct 26.

1HIV-1 Immunopathogenesis Laboratory, The Wistar Institute, Philadelphia, PA, USA.

Background: Antiretroviral therapy (ART)-mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication.

Methods: A total of 23 HIV type 1 (HIV-1)-infected, virologically suppressed subjects receiving ART (CD4(+) T-cell count, >450 cells/μL) were randomly assigned to have 180 μg/week (for arm A) or 90 μg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg-interferon alfa-2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologic failure (viral load, ≥ 400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed.

Results: At week 12 of Peg-interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P = .0088; arm B, P = .0010; combined arms, P < .0001). Over 24 weeks, both arms had lower proportions of subjects who had viral load, compared with the proportion of subjects in a historical control group (arm A, P = .0046; arm B, P = .0011). Subjects who had a sustained viral load of <400 copies/mL had decreased levels of integrated HIV DNA (P = .0313) but increased residual viral loads (P = .0078), compared with subjects who experienced end-point failure.

Conclusions: Peg-interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication.

Clinical Trials Registration: NCT00594880.
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http://dx.doi.org/10.1093/infdis/jis663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532820PMC
January 2013

Concurrent measures of total and integrated HIV DNA monitor reservoirs and ongoing replication in eradication trials.

AIDS 2012 Nov;26(18):2295-306

Division of Transfusion Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, USA.

Objectives: Interest in targeting HIV reservoirs is fueling trials that may decrease reservoir size and/or induce viral replication. Therefore, we aimed to develop strategies to sensitively measure changes in these parameters in patients on and off antiretroviral therapy (ART). Achieving these goals may help evaluate the effects of future clinical trials.

Design: To determine the relationship between measurements of total and integrated HIV DNA and their role as markers of reservoir size and ongoing replication, these parameters were measured during the first year of ART, during long-term effective ART, and during a clinical trial aimed at targeting reservoirs.

Methods: Total and integrated HIV DNA were measured in patient samples using quantitative PCR techniques. CD4(+)T cell counts and plasma viremia were also monitored.

Results: Unintegrated HIV DNA became undetectable during the first year of ART. Total and integrated HIV DNA levels were generally equal in well controlled patients on ART, and low-level plasma viremia correlated best with integration measures. Finally, patients who controlled plasma viremia (<400 copies/ml) during interferon-α monotherapy exhibited a decrease in the level of integrated but not total HIV DNA and a rise in the ratio of total to integrated HIV DNA over time.

Conclusion: Our findings suggest that appearance of unintegrated HIV DNA reflects residual HIV expression and de-novo reverse transcription, providing insight into the mechanism by which interferon-α reduces the HIV reservoir. We conclude that concurrent measurements of total and integrated HIV DNA provide information regarding reservoir size and ongoing replication in trials targeting HIV.
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http://dx.doi.org/10.1097/QAD.0b013e32835a5c2fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692807PMC
November 2012
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