IDENTIFICATION AND ASSESSMENT OF LONGITUDINAL BIOMARKERS USING FRAILTY MODELS IN SURVIVAL ANALYSIS

A biomarker is a measurement which can be used as a predictor or sometimes even a surrogate for a biological endpoint that directly measures a patient's disease or survival status. Biomarkers are often measured over time and so are referred to as longitudinal biomarkers. Biomarkers are of public health interest because they can provide early detection of life threatening or fatal diseases. It is important in public health to be able to identify biomarkers to predict survival for patients because it can reduce the time and cost necessary to resolve the study question or used to identify subsets of patients who would be appropriate candidates for the administration of a targeted therapy. In this dissertation, we introduce a method employing a frailty model to identify longitudinal biomarkers or surrogates for a time to event outcome. Our method is an extension of earlier work by Wulfson, Tsiatis, and Song where it was assumed that the event times have the same baseline hazard. In our method, we allow random effects to be present in both the longitudinal biomarker and underlying survival function. The random effect in the biomarker is introduced via an explicit term while the random effect in the underlying survival function is introduced by the inclusion of frailty parameters into the model. We use simulations to explore how the number of individuals, the number of time points per individual and the functional form of the random effects from the longitudinal biomarkers influence the power to detect the association of the longitudinal biomarker and the survival time. We also explore effect of missingness on how a biomarker predicts a time to event outcome. We conclude that for a given sample size, the biomarker effectiveness for relatively small numbers of subjects and large numbers of observed time points is better than for relatively large numbers of subjects and small numbers of observed time points. We also conclude that when the missing data mechanism is missing at random (MAR), our method works reasonably well. However, when the missing data mechanism is non-ignorable, our method doesn't perform well in determining whether or not potential biomarkers are good predictors of a time to event outcome. Finally, we apply our method to liver cirrhosis data and conclude that prothrombin is a good predictor of time to liver cirrhosis and thus, can be used as a potential surrogate for liver failure

Comparison of heavy-ion transport simulations: Collision integral with pions and Δ resonances in a box

We compare ten transport codes for a system confined in a box, aiming at improved handling of the production of $\Delta$ resonances and pions, which is indispensable for constraining high-density symmetry energy from observables such as the $\pi^-/\pi^+$ yield ratio in heavy-ion collisions. The system in a box is initialized with nucleons at saturation density and at 60 MeV temperature. The reactions $NN\leftrightarrow N\Delta$ and $\Delta\leftrightarrow N\pi$ are implemented, but the Pauli blocking and the mean-field potential are deactivated in the present comparison. Results are compared to those from the two reference cases of a chemically equilibrated ideal gas mixture and of the rate equation. In the results of the numbers of $\Delta$ and $\pi$, deviations from the reference values are observed in many codes, and they depend significantly on the size of the time step. These deviations are tied to different ways in ordering the sequence of collisions and decays, that take place in the same time step. Better agreements are seen in the reaction rates and the number ratios among the isospin species of $\Delta$ and $\pi$. These are, however, affected by the correlations, which are absent in the Boltzmann equation, but are induced by the way particle scatterings are treated in transport calculations. The uncertainty in the transport-code predictions of the $\pi^-/\pi^+$ ratio for the system initialized at n/p = 1.5, after letting the existing $\Delta$ resonances decay, is found to be within a few percent, which is sufficiently small so that it does not strongly impact constraining the high-density symmetry energy from heavy-ion collisions. Most of the sources of uncertainties have been understood, and individual codes may be further improved. This investigation will be extended in the future to heavy-ion collisions to ensure the problems identified here remain under control.Comment: 36 pages, 27 figures; a new Fig. 21 and revised results from some codes, achieving improved and consistent understandin

Acute-on-chronic kidney injury at hospital discharge is associated with long-term dialysis and mortality

Existing chronic kidney disease (CKD) is among the most potent predictors of postoperative acute kidney injury (AKI). Here we quantified this risk in a multicenter, observational study of 9425 patients who survived to hospital discharge after major surgery. CKD was defined as a baseline estimated glomerular filtration rate <45ml/min per 1.73m2. AKI was stratified according to the maximum simplified RIFLE classification at hospitalization and unresolved AKI defined as a persistent increase in serum creatinine of more than half above the baseline or the need for dialysis at discharge. A Cox proportional hazard model showed that patients with AKI-on-CKD during hospitalization had significantly worse long-term survival over a median follow-up of 4.8 years (hazard ratio, 3.3) than patients with AKI but without CKD. The incidence of long-term dialysis was 22.4 and 0.17 per 100 person-years among patients with and without existing CKD, respectively. The adjusted hazard ratio for long-term dialysis in patients with AKI-on-CKD was 19.8 compared to patients who developed AKI without existing CKD. Furthermore, AKI-on-CKD but without kidney recovery at discharge had a worse outcome (hazard ratios of 4.6 and 213, respectively) for mortality and long-term dialysis as compared to patients without CKD or AKI. Thus, in a large cohort of postoperative patients who developed AKI, those with existing CKD were at higher risk for long-term mortality and dialysis after hospital discharge than those without. These outcomes were significantly worse in those with unresolved AKI at discharge

Comparison of heavy-ion transport simulations: Collision integral in a box

Simulations by transport codes are indispensable to extract valuable physical information from heavy-ion collisions. In order to understand the origins of discrepancies among different widely used transport codes, we compare 15 such codes under controlled conditions of a system confined to a box with periodic boundary, initialized with Fermi-Dirac distributions at saturation density and temperatures of either 0 or 5 MeV. In such calculations, one is able to check separately the different ingredients of a transport code. In this second publication of the code evaluation project, we only consider the two-body collision term; i.e., we perform cascade calculations. When the Pauli blocking is artificially suppressed, the collision rates are found to be consistent for most codes (to within 1 % or better) with analytical results, or completely controlled results of a basic cascade code. In orderto reach that goal, it was necessary to eliminate correlations within the same pair of colliding particles that can be present depending on the adopted collision prescription. In calculations with active Pauli blocking, the blocking probability was found to deviate from the expected reference values. The reason is found in substantial phase-space fluctuations and smearing tied to numerical algorithms and model assumptions in the representation of phase space. This results in the reduction of the blocking probability in most transport codes, so that the simulated system gradually evolves away from the Fermi-Dirac toward a Boltzmann distribution. Since the numerical fluctuations are weaker in the Boltzmann-Uehling-Uhlenbeck codes, the Fermi-Dirac statistics is maintained there for a longer time than in the quantum molecular dynamics codes. As a result of this investigation, we are able to make judgements about the most effective strategies in transport simulations for determining the collision probabilities and the Pauli blocking. Investigation in a similar vein of other ingredients in transport calculations, like the mean-field propagation or the production of nucleon resonances and mesons, will be discussed in the future publications

Human Herpesvirus 8 Interferon Regulatory Factor-Mediated BH3-Only Protein Inhibition via Bid BH3-B Mimicry

Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of host cells. For HHV-8, viral interferon regulatory factor-1 (vIRF-1) contributes to this process in part via inhibitory interactions with BH3-only protein (BOP) Bim, recently identified as an interaction partner of vIRF-1. Here we recognize that the Bim-binding domain (BBD) of vIRF-1 resembles a region (BH3-B) of Bid, another BOP, which interacts intramolecularly with the functional BH3 domain of Bid to inhibit it pro-apoptotic activity. Indeed, vIRF-1 was found to target Bid in addition to Bim and to interact, via its BBD region, with the BH3 domain of each. In functional assays, BBD could substitute for BH3-B in the context of Bid, to suppress Bid-induced apoptosis in a BH3-binding-dependent manner, and vIRF-1 was able to protect transfected cells from apoptosis induced by Bid. While vIRF-1 can mediate nuclear sequestration of Bim, this was not the case for Bid, and inhibition of Bid and Bim by vIRF-1 could occur independently of nuclear localization of the viral protein. Consistent with this finding, direct BBD-dependent inactivation by vIRF-1 of Bid-induced mitochondrial permeabilization was demonstrable in vitro and isolated BBD sequences were also active in this assay. In addition to Bim and Bid BH3 domains, BH3s of BOPs Bik, Bmf, Hrk, and Noxa also were found to bind BBD, while those of both pro- and anti-apoptotic multi-BH domain Bcl-2 proteins were not. Finally, the significance of Bid to virus replication was demonstrated via Bid-depletion in HHV-8 infected cells, which enhanced virus production. Together, our data demonstrate and characterize BH3 targeting and associated inhibition of BOP pro-apoptotic activity by vIRF-1 via Bid BH3-B mimicry, identifying a novel mechanism of viral evasion from host cell defenses

Search for the Chiral Magnetic Effect in Au+Au collisions at sNN=27\sqrt{s_{_{\rm{NN}}}}=27 GeV with the STAR forward Event Plane Detectors

A decisive experimental test of the Chiral Magnetic Effect (CME) is considered one of the major scientific goals at the Relativistic Heavy-Ion Collider (RHIC) towards understanding the nontrivial topological fluctuations of the Quantum Chromodynamics vacuum. In heavy-ion collisions, the CME is expected to result in a charge separation phenomenon across the reaction plane, whose strength could be strongly energy dependent. The previous CME searches have been focused on top RHIC energy collisions. In this Letter, we present a low energy search for the CME in Au+Au collisions at $\sqrt{s_{_{\rm{NN}}}}=27$ GeV. We measure elliptic flow scaled charge-dependent correlators relative to the event planes that are defined at both mid-rapidity $|\eta|<1.0$ and at forward rapidity $2.1 < |\eta|<5.1$. We compare the results based on the directed flow plane ($\Psi_1$) at forward rapidity and the elliptic flow plane ($\Psi_2$) at both central and forward rapidity. The CME scenario is expected to result in a larger correlation relative to $\Psi_1$ than to $\Psi_2$, while a flow driven background scenario would lead to a consistent result for both event planes[1,2]. In 10-50\% centrality, results using three different event planes are found to be consistent within experimental uncertainties, suggesting a flow driven background scenario dominating the measurement. We obtain an upper limit on the deviation from a flow driven background scenario at the 95\% confidence level. This work opens up a possible road map towards future CME search with the high statistics data from the RHIC Beam Energy Scan Phase-II.Comment: main: 8 pages, 5 figures; supplementary material: 2 pages, 1 figur

Event-by-event correlations between Λ\Lambda (Λˉ\bar{\Lambda}) hyperon global polarization and handedness with charged hadron azimuthal separation in Au+Au collisions at sNN=27 GeV\sqrt{s_{\text{NN}}} = 27 \text{ GeV} from STAR

Global polarizations ($P$) of $\Lambda$ ($\bar{\Lambda}$) hyperons have been observed in non-central heavy-ion collisions. The strong magnetic field primarily created by the spectator protons in such collisions would split the $\Lambda$ and $\bar{\Lambda}$ global polarizations ($\Delta P = P_{\Lambda} - P_{\bar{\Lambda}} < 0$). Additionally, quantum chromodynamics (QCD) predicts topological charge fluctuations in vacuum, resulting in a chirality imbalance or parity violation in a local domain. This would give rise to an imbalance ($\Delta n = \frac{N_{\text{L}} - N_{\text{R}}}{\langle N_{\text{L}} + N_{\text{R}} \rangle} \neq 0$) between left- and right-handed $\Lambda$ ($\bar{\Lambda}$) as well as a charge separation along the magnetic field, referred to as the chiral magnetic effect (CME). This charge separation can be characterized by the parity-even azimuthal correlator ($\Delta\gamma$) and parity-odd azimuthal harmonic observable ($\Delta a_{1}$). Measurements of $\Delta P$, $\Delta\gamma$, and $\Delta a_{1}$ have not led to definitive conclusions concerning the CME or the magnetic field, and $\Delta n$ has not been measured previously. Correlations among these observables may reveal new insights. This paper reports measurements of correlation between $\Delta n$ and $\Delta a_{1}$, which is sensitive to chirality fluctuations, and correlation between $\Delta P$ and $\Delta\gamma$ sensitive to magnetic field in Au+Au collisions at 27 GeV. For both measurements, no correlations have been observed beyond statistical fluctuations.Comment: 10 pages, 10 figures; paper from the STAR Collaboratio

Hyperon polarization along the beam direction relative to the second and third harmonic event planes in isobar collisions at sNN\sqrt{s_{NN}} = 200 GeV

The polarization of $\Lambda$ and $\bar{\Lambda}$ hyperons along the beam direction has been measured relative to the second and third harmonic event planes in isobar Ru+Ru and Zr+Zr collisions at $\sqrt{s_{NN}}$ = 200 GeV. This is the first experimental evidence of the hyperon polarization by the triangular flow originating from the initial density fluctuations. The amplitudes of the sine modulation for the second and third harmonic results are comparable in magnitude, increase from central to peripheral collisions, and show a mild $p_T$ dependence. The azimuthal angle dependence of the polarization follows the vorticity pattern expected due to elliptic and triangular anisotropic flow, and qualitatively disagree with most hydrodynamic model calculations based on thermal vorticity and shear induced contributions. The model results based on one of existing implementations of the shear contribution lead to a correct azimuthal angle dependence, but predict centrality and $p_T$ dependence that still disagree with experimental measurements. Thus, our results provide stringent constraints on the thermal vorticity and shear-induced contributions to hyperon polarization. Comparison to previous measurements at RHIC and the LHC for the second-order harmonic results shows little dependence on the collision system size and collision energy.Comment: 6 pages, 5 figures, Published in Physical Review Letter

Measurement of Λ4H\rm ^4_{\Lambda}H and Λ4He\rm ^4_{\Lambda}He binding energy in Au+Au collisions at sNN\sqrt{s_\mathrm{NN}} = 3 GeV

Measurements of mass and $\Lambda$ binding energy of $\rm ^4_{\Lambda}H$ and $\rm ^4_{\Lambda}He$ in Au+Au collisions at $\sqrt{s_{_{\rm NN}}}=3$ GeV are presented, with an aim to address the charge symmetry breaking (CSB) problem in hypernuclei systems with atomic number A = 4. The $\Lambda$ binding energies are measured to be $\rm 2.22\pm0.06(stat.) \pm0.14(syst.)$ MeV and $\rm 2.38\pm0.13(stat.) \pm0.12(syst.)$ MeV for $\rm ^4_{\Lambda}H$ and $\rm ^4_{\Lambda}He$, respectively. The measured $\Lambda$ binding-energy difference is $\rm 0.16\pm0.14(stat.)\pm0.10(syst.)$ MeV for ground states. Combined with the $\gamma$-ray transition energies, the binding-energy difference for excited states is $\rm -0.16\pm0.14(stat.)\pm0.10(syst.)$ MeV, which is negative and comparable to the value of the ground states within uncertainties. These new measurements on the $\Lambda$ binding-energy difference in A = 4 hypernuclei systems are consistent with the theoretical calculations that result in $\rm \Delta B_{\Lambda}^4(1_{exc}^{+})\approx -\Delta B_{\Lambda}^4(0_{g.s.}^{+})<0$ and present a new method for the study of CSB effect using relativistic heavy-ion collisions.Comment: 8 pages, 5 figure