Exposure density sampling: Dynamic matching with respect to a time-dependent exposure

Estimating the potential risk associated with an exposure occurring over time requires complex statistical techniques, since ignoring the time from study entry until the exposure leads to potentially seriously biased effect estimates. A prominent example is estimating the effect of hospital-acquired infections on adverse outcomes in patients admitted to the intensive care unit. Exposure density sampling has been proposed as an approach to dynamic matching with respect to a time-dependent exposure. Firstly, exposure density sampling can be useful to reduce the workload of study follow up, as it includes all exposed but only a subset of the not yet exposed individuals. Secondly, it can help to obtain a comparable control group by including propensity score matching. In the present article, we provide the theoretical justification that data obtained by exposure density sampling can be analyzed as a left-truncated cohort. It is shown that exposure density sampling allows estimation of the effect of a time-dependent exposure as well as further baseline covariates on a subsequent event, with only minor loss in precision as compared with a full cohort analysis. The sampling is applied to a real data example (hospital-acquired infections in intensive care units) and in a simulation study. We also provide an estimate of the loss in precision in terms of an increased standard error in the reduced data set after exposure density sampling as compared with the full cohort.     

Time-dependent inhibition (TDI) of CYP1A2 by a CYP3A4-mediated reactive metabolite: proposal for a novel mechanism of irreversible TDI by a non-suicide substrate

1. The purpose of this study was to clarify the mechanism of DSP-1053 time-dependent inhibition (TDI) for CYP1A2.

2. DSP-1053 inhibited time- and concentration-dependently CYP1A2 activity in human liver microsomes even in a dilution assay. However, DSP-1053 was not metabolized by recombinant human CYP1A2. These findings indicate that the inhibitory effect of DSP-1053 on CYP1A2 does not follow a general mechanism-based inhibition (MBI) because it did not seem to be a suicide substrate.

3. In fact, CYP1A2 was not inhibited with DSP-1053 pre-incubation in recombinant human CYP1A2. On the other hand, CYP1A2 was potently inhibited after pre-incubation with DSP-1053 in a mixture of human recombinant CYP1A2 and CYP3A4. In addition, DSP-1053 TDI of CYP1A2 in human liver microsomes was drastically reduced not only by addition of a CYP3A4 inhibitor, but also by addition of potassium cyanide (KCN), which is a trapping agent for iminium ions. We also confirmed in this study that CYP1A2 suicide inhibition by DSP-1053 metabolites generated by CYP3A4 had only minimal role in DSP-1053 TDI of CYP1A2.

4. In conclusion, a possible mechanism for DSP-1053 TDI of CYP1A2 is that DSP-1053 iminium ion, which is generated by CYP3A4, departs from CYP3A4 without inhibiting it and covalently binds to CYP1A2.     

Evolutionary selection between alternative modes of gene regulation

Microorganisms employ a wealth of gene regulatory mechanisms to adjust their growth programs to variations in the environment. It was pointed out long ago [Savageau M (1977) Proc Natl Acad Sci USA 74: 5647–5651] that the particular mode of gene regulation employed may be correlated with the “demand” on the regulated gene, i.e., how frequently the gene product is needed in its natural habitat. An evolutionary “use-it-or-lose-it” principle was proposed to govern the choice of gene regulatory strategies. Here, we examine quantitatively the forces selecting for and against two opposing modes of gene regulation, in the context of an evolutionary model that takes genetic drift, mutation, and time-dependent selection into account. We consider the effect of time-dependent selection, with periods of strong selection alternating with periods of neutral evolution. Using a variety of analytical methods, we find the effective population size and the typical time scale of environmental variations to be key parameters determining the fitness advantage of the different modes of regulation. Our results support Savageau''s use-it-or-lose-it principle for small populations with long time scales of environmental variations and support a complementary “wear-and-tear” principle for the opposite situation.     

Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

AIMS

To investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data.

METHODS

The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo noscapine–warfarin interaction magnitude from in vitro data.

RESULTS

Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC₅₀ of 10.8 ± 2.5 µm and 13.3 ± 1.2 µm. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with K_i value of 8.8 µm, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with K_i value of 5.2 µm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (K_I and k_inact) were calculated to be 9.3 µm and 0.06 min⁻¹ for CYP3A4 and 8.9 µm and 0.014 min⁻¹ for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using C_max or 0.5% and 0.4% using unbound C_max with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using C_max or 41.8% and 32.7% using unbound C_max with TDI prediction equation.

CONCLUSIONS

TDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction.     

Quantifying the impact of survivor treatment bias in observational studies

RATIONALE: Observational cohort studies are frequently used to measure the impact of therapies on the time to a particular outcome. Treatment often has a time-variant nature since it is frequently initiated at varying times during a patient's follow-up. Studies in the medical literature frequently ignore the time-dependent nature of treatment exposure. Survivor treatment bias can arise when the time dependent nature of treatment exposure is ignored since patients who survived to receive treatment may be healthier than patients who died prior to receipt of treatment. AIMS AND OBJECTIVES: The objective of the current study was to explicitly quantify the magnitude of survivor-treatment bias. METHODS: Monte Carlo simulations using parameters obtained from an analysis of patients admitted to hospital with a diagnosis of acute myocardial infarction in Ontario, Canada. RESULTS AND CONCLUSIONS: When the true treatment was null (hazard ratio of 1), estimated treatment effects varied from a 4% reduction in mortality to a reduction in mortality of 27% when the time varying nature of the treatment was ignored. Furthermore, survivor-treatment bias increased as the time required foe exposed patients to receive treatment increased. Similarly, survivor treatment bias was amplified as exposure was defined to be exposure at any time prior to mortality compared to exposure within a fixed time interval starting at the time origin. Ignoring the time-dependent nature of treatment results in overly optimistic estimates of treatment effects. Depending on the period required for patients to initiate therapy, treatments with no effect on survival can appear to be strongly associated with improved survival. The current study is the first to explicitly quantify the magnitude of bias that results from ignoring the time-varying nature of treatment exposure in survival studies.     

A covariate-specific time-dependent receiver operating characteristic curve for correlated survival data

Several studies for the clinical validity of circulating tumor cells (CTCs) in metastatic breast cancer were conducted showing that it is a prognostic biomarker of overall survival. In this work, we consider an individual patient data meta-analysis for nonmetastatic breast cancer to assess the discrimination of CTCs regarding the risk of death. Data are collected in several centers and present correlated failure times for subjects of the same center. However, although the covariate-specific time-dependent receiver operating characteristic (ROC) curve has been widely used for assessing the performance of a biomarker, there is no methodology yet that can handle this specific setting with clustered censored failure times. We propose an estimator for the covariate-specific time-dependent ROC curves and area under the ROC curve when clustered failure times are detected. We discuss the assumptions under which the estimators are consistent and their interpretations. We assume a shared frailty model for modeling the effect of the covariates and the biomarker on the outcome in order to account for the cluster effect. A simulation study was conducted and it shows negligible bias for the proposed estimator and a nonparametric one based on inverse probability censoring weighting, while a semiparametric estimator, ignoring the clustering, is markedly biased. Finally, in our application to breast cancer data, the estimation of the covariate-specific area under the curves illustrates that the CTCs discriminate better patients with inflammatory tumor than patients with noninflammatory tumor, with respect to their risk of death.     

Time-Dependent Barriers and First-Passage Times-Different Types of Neuronal Models

Abstract

To study the phenomenon of spike discharge in a single neuron, first-passage time density of the membrane potential to cross or reach the threshold value in different situations is analyzed. The neuron is taken as a leaky integrator and the inputs are due to Poisson events occurring independently. Closed solutions using the compensation method and imbedding techn~ques are arrived at. Using Keilson’s limiting procedure, diffusion processes with boundaries are solved. To simulate the refractory period of the neuron, thresholds moving linearly or exponentially with time are considered. Very interesting Wald identities are obtained in the case of jump processes which go over to the corresponding identities for diffusion processes obtained by a limiting procedure.     

Time-Dependent Damage Investigation of Rock Mass in an In Situ Experimental Tunnel

In underground tunnels or caverns, time-dependent deformation or failure of rock mass, such as extending cracks, gradual rock falls, etc., are a costly irritant and a major safety concern if the time-dependent damage of surrounding rock is serious. To understand the damage evolution of rock mass in underground engineering, an in situ experimental testing was carried out in a large belowground tunnel with a scale of 28.5 m in width, 21 m in height and 352 m in length. The time-dependent damage of rock mass was detected in succession by an ultrasonic wave test after excavation. The testing results showed that the time-dependent damage of rock mass could last a long time, i.e., nearly 30 days. Regression analysis of damage factors defined by wave velocity, resulted in the time-dependent evolutional damage equation of rock mass, which corresponded with logarithmic format. A damage viscoelastic-plastic model was developed to describe the exposed time-dependent deterioration of rock mass by field test, such as convergence of time-dependent damage, deterioration of elastic modules and logarithmic format of damage factor. Furthermore, the remedial measures for damaged surrounding rock were discussed based on the measured results and the conception of damage compensation, which provides new clues for underground engineering design.     

Comparison of the electrophysiology and morphology of layers III and II neurons of the rat medial entorhinal cortex in vitro

The basic membrane characteristics of neurons in layers II and III of the medial entorhinal cortex (MEA) were recorded using the intracellular current clamp technique in in vitro slices of the rat brain. Two types of cells were distinguished according to the presence of a time-dependent inward rectification (SAG current) with hyperpolarizing current pulses. The cells in which this inward rectification was not observed (No-SAG cells) had a larger input resistance, a more negative resting membrane potential and a more depolarized firing threshold. They more often displayed a strongly adapting firing pattern, and their action potentials had a slower decay rate and lacked a depolarizing afterpotential, compared with the SAG cells. SAG cells typically had a prominent rebound depolarization at the end of a hyperpolarizing current and membrane potential oscillations (7 Hz) upon subthreshold depolarizations. Cs⁺ blocked the time-dependent inward rectification. The rebound depolarization persisted, even in the presence of tetrodotoxin. Biocytin labelling showed that layer III consisted mainly of pyramidal-shaped cells. Most layer III cells were of the No-SAG type. All cells in layer II, stellate and pyramidal cells, were classified as SAG cells. We conclude that the cells in MEA layers II and III display different electroresponsiveness, but that this appears to be more related to the layer where they are located than to a specific morphology. As layer III consisted mainly of cells of the No-SAG type, we suggest that layer III cells are less excitable than the SAG type layer II cells.