Hyejeong Jang

The outcome of acute respiratory distress syndrome in relation to body mass index and diabetes mellitus.

OBJECTIVE To determine the 28 day mortality of patients with ARDS in relation to body mass index (BMI) and presence diabetes mellitus (DM). DESIGN Retrospective cohort study of patients enrolled in the ARDS Network randomized controlled trials. RESULTS 2914 patients were enrolled in these trials. 112 patients were underweight (BMI < 18.5), 948 patients were normal range (18.5 ≤ BMI < 25.0), 801 patients were overweight (25.0 ≤ BMI < 30.0), 687 patients were obese (30.0 ≤ BMI < 40.0), and 175 patients were severely obese (BMI ≥ 40.0). 469 patients had DM. There was no significant difference in the 28 day mortality in relation to BMI or presence of DM (underweight adjusted OR, 1.217; 95% CI, 0.749-1.979; overweight adjusted OR, 0.887; 95% CI, 0.696-1.131; obese adjusted OR, 0.812; 95% CI, 0.624-1.056; severely obese adjusted OR, 1.102; 95% CI, 0.716-1.695; and DM adjusted OR, 0.938; 95% CI, 0.728-1.208). CONCLUSIONS The short term mortality in patients with ARDS is not affected by BMI or the presence of DM.

Piecewise nonlinear mixed-effects models for modeling cardiac function and assessing treatment effects

Mixed-effects model is an efficient tool for analyzing longitudinal data. The random effects in a mixed-effects model can be used to capture the correlations among repeated measurements within a subject. Mixed effects model can be used to describe individual response profile as well as population response profile. In this manuscript, we apply mixed-effects models to the repeated measurements of cardiac function variables including heart rate, coronary flow, and left ventricle developed pressure (LVDP) in the isolated, Langendorff-perfused hearts of glutathione s-transferase P1/P2 (GSTP) gene knockout and wild-type mice. Cardiac function was measured before and during ischemia/reperfusion injury in these hearts. To describe the dynamics of each cardiac function variable during the entire experiment, we developed piecewise nonlinear mixed-effects models and a change point nonlinear mixed effect model. These models can be used to examine how cardiac function variables were altered by ischemia/reperfusion-induced injury and to compare the cardiac function variable between genetically engineered (null or transgenic) mice and wild-type mice. Hypothesis tests were constructed to evaluate the impact of deletion of GSTP gene for different cardiac function variables. These findings provide a new application for mixed-effects models in physiological and pharmacological studies of the isolated Langendorff-perfused heart.

Incidence, Etiology and Outcome of Pleural Effusions in Allogeneic Hematopoietic Stem Cell Transplantation

Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity−mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 − 869) post‐HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 − 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, ≤7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341–E347, 2016.

Bayesian lead time estimation for the Johns Hopkins Lung Project data.

Problem statement: Lung cancer screening using X-rays has been controversial for many years. A major concern is whether lung cancer screening really brings any survival benefits, which depends on effective treatment after early detection. The problem was analyzed from a different point of view and estimates were presented of the projected lead time for participants in a lung cancer screening program using the Johns Hopkins Lung Project (JHLP) data. Method: The newly developed method of lead time estimation was applied where the lifetime T was treated as a random variable rather than a fixed value, resulting in the number of future screenings for a given individual is a random variable. Using the actuarial life table available from the United States Social Security Administration, the lifetime distribution was first obtained, then the lead time distribution was projected using the JHLP data. Results: The data analysis with the JHLP data shows that, for a male heavy smoker with initial screening ages at 50, 60, and 70, the probability of no-early-detection with semiannual screens will be 32.16%, 32.45%, and 33.17%, respectively; while the mean lead time is 1.36, 1.33 and 1.23 years. The probability of no-early-detection increases monotonically when the screening interval increases, and it increases slightly as the initial age increases for the same screening interval. The mean lead time and its standard error decrease when the screening interval increases for all age groups, and both decrease when initial age increases with the same screening interval. Conclusion: The overall mean lead time estimated with a random lifetime T is slightly less than that with a fixed value of T. This result is hoped to be of benefit to improve current screening programs.

NormalGammaBernoulli peak detection for analysis of comprehensive two-dimensional gas chromatography mass spectrometry data

Compared to other analytical platforms, comprehensive two-dimensional gas chromatography coupled with mass spectrometry (GC×GC-MS) has much increased separation power for analysis of complex samples and thus is increasingly used in metabolomics for biomarker discovery. However, accurate peak detection remains a bottleneck for wide applications of GC×GC-MS. Therefore, the normal-exponential-Bernoulli (NEB) model is generalized by gamma distribution and a new peak detection algorithm using the normal-gamma-Bernoulli (NGB) model is developed. Unlike the NEB model, the NGB model has no closed-form analytical solution, hampering its practical use in peak detection. To circumvent this difficulty, three numerical approaches, which are fast Fourier transform (FFT), the first-order and the second-order delta methods (D1 and D2), are introduced. The applications to simulated data and two real GC×GC-MS data sets show that the NGB-D1 method performs the best in terms of both computational expense and peak detection performance.

Multistate models on pleural effusion after allogeneic hematopoietic stem cell transplantation

A multistate model is more complicated than competing risk models and composed of finite number of states and transitions between states. Unlike competing risk models, this model has the ability to assess the effect of occurrence order of time-to-event data. Pleural effusion (PE) is a severe complication that often occurs after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients develop pleural effusion during the first 100 days after allogeneic HSCT and graft-versus-host disease (GVHD) occurs either before or after the development of PE, implying that the occurrence order of PE and GVHD (i.e., PE after GVHD vs. GVHD after PE) would influence on the incidence, risk factors and mortality of pleural effusion. One can use either Cox proportional models or competing risk models to evaluate these values, but neither method is able to incorporate the occurrence order of incidence into the model. To resolve this difficulty, we developed a multistate model describing several possible events and event-related dependences and applied to a retrospective study of 606 patients, including eight covariates.

The effect of demographics and patient location on the outcome of patients with acute respiratory distress syndrome

OBJECTIVE: Outcome of acute respiratory distress syndrome (ARDS) in relation to age, gender, race, pre-Intensive Care Unit (ICU) location, and type of ICU. METHODS: Retrospective cohort study of patients enrolled in the ARDS network randomized controlled trials. RESULTS: A total of 2914 patients were included in these trials. Outcomes were adjusted to baseline covariates including APACHE III score, vasopressor use, cause of lung injury, lung injury score, diabetes, cancer status, body mass index, and study ID. Older patients had significantly higher mortality at both 28- and 60-day (odds ratio [OR] 2.59 [95% confidence interval [CI]: 2.12-3.18] P < 0.001 and 2.79, 95% CI: 2.29-3.39, P < 0.001, respectively); less ICU and ventilator free days (relative risk [RR] 0.92, 95% CI: 0.87-0.96, P < 0.001 and 0.92, 95% CI: 0.88-0.96, P < 0.001, respectively). For preadmission location, the 28- and 60-day mortality were lower if the patient was admitted from the operating room (OR)/recovery room (OR 0.65, 95% CI: 0.44-0.95, P = 0.026; and OR = 0.66, 95% CI: 0.46-0.95, P = 0.025, respectively) or emergency department (OR = 0.78, 95% CI: 0.61-0.99, P = 0.039; and OR = 0.71, 95% CI: 0.56-0.89, P = 0.004, respectively), but no statistical differences in ICU and ventilator free days between different preadmission locations. Races other than white and black had a statistically higher mortality (28- and 60-day mortality: OR = 1.47, 95% CI: 1.09-1.98, P = 0.011; and OR 1.53, 95% CI: 1.15-2.04, P = 0.004, respectively). Between whites and blacks, females and males there were no statistically significant differences in all outcomes. CONCLUSION: Older patients and races other than blacks and whites have higher mortality associated with ARDS. Mortality is affected by patients preadmission location. There are no differences in outcome in relation to the type of ICU, gender, or between blacks and whites.

A phase II study of tacrolimus and thymoglobulin as graft-versus-host-disease prophylaxis in related donor allogeneic hematopoietic cell transplantation

Ayalew Tefferi , Sravanthi Lavu , Mythri Mudireddy , Terra L. Lasho, Christy M. Finke, Naseema Gangat , Animesh Pardanani, Curtis A. Hanson, Carmela Mannarelli, Paola Guglielmelli, Alessandro M. Vannucchi Division of Hematology, Mayo Clinic, Rochester, Minnesota Division of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy

Effect of ARDS Severity and Etiology on Short-Term Outcomes

BACKGROUND: We evaluated the outcome of subjects with ARDS in relation to etiology and severity in a retrospective cohort study of the ARDS Network randomized controlled trials. The primary outcome was 28-d mortality. The secondary outcomes were 60-d mortality and ventilator- and ICU-free days. For severity of ARDS, subjects were stratified according to PaO2/FIO2. The etiology of ARDS was classified into sepsis, pneumonia, aspiration, trauma, and others. RESULTS: A total of 2,914 subjects were included in these trials. Outcomes were modeled with multivariable regressions adjusted for baseline covariates, age, sex, race, Acute Physiology and Chronic Health Evaluation III (APACHE III), vasopressor use, modified lung injury score, diabetes mellitus, cancer status, body mass index, pre-ICU location, ICU location, and study. There was no statistically significant difference in 28-d mortality in relation to ARDS severity. Subjects with trauma, compared with other etiologies of ARDS, had significantly lower mortality at 28 d (odds ratio [OR] = 0.47, 95% CI 0.26–0.83, P = .01). Sixty-day mortality was significantly lower for trauma subjects and those with severe ARDS group (OR = 0.5, 95% CI 0.3–0.85, P = .01 and OR = 0.71, 95% CI 0.52–0.98, P = .034, respectively). There were statistically significantly more ICU-free days and ventilator-free days for the aspiration group (OR = 1.09, 95% CI 1.02–1.17, P = .01 and OR = 1.09, 95% CI 1.02–1.16, P = .01, respectively). There was no statistically significant difference in ICU-free days or ventilator-free days in relation to severity of ARDS. CONCLUSIONS: Severity of ARDS based on PaO2/FIO2 did not impact 28-d mortality, ventilator-free days, or ICU-free days. Among the etiologies of ARDS, trauma subjects had the lowest 28- and 60-d mortality, whereas subjects with aspiration had more ICU-free days and ventilator-free days.

Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells

Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20-30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment.