Response to: 'Bodyweight-adjustments introduce significant correlations between CYP3A metrics and tacrolimus clearance'.
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ABSTRACT:
SUBMITTER: Vanhove T
PROVIDER: S-EPMC5427232 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
Publications
Response to: 'Bodyweight-adjustments introduce significant correlations between CYP3A metrics and tacrolimus clearance'.
Vanhove Thomas T Annaert Pieter P Kuypers Dirk R J DRJ
British journal of clinical pharmacology 20170220 6
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Project description:Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1-17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information.
| S-EPMC6597607 | biostudies-literature
Project description:ObjectivesInterpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D).MethodsWe performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed.ResultsOf the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (P = 0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 (interquartile range: 147.6-267.5) (ng/ml)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), P = 0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes.ConclusionThese data indicate that a composite CYP3A phenotype incorporating both increase and decrease variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.
| S-EPMC9177686 | biostudies-literature
Project description:Water scarcity is a global challenge affecting billions of people worldwide. This study systematically assesses differences in the estimation of the global population exposed to water scarcity based on 7 water scarcity indicators and 11 Environmental Flow Requirements (EFR) evaluated at various spatial and temporal resolutions. All indicators show an increase in water scarcity since 1901. However, considering monthly average water scarcity estimates spatially aggregated at the basin scale found 35% less population exposed than estimates based on a distributed grid over the landscape. Estimates temporally disaggregated to consider water scarcity for at least one month a year found 50% (tenfold) larger population exposed compared to average monthly (annual) estimates. The study illustrates that estimates of the impacts of water scarcity are an artifact of how water scarcity is defined and calculated. This suggests caution is needed when relying on a single method and emphasizes the importance of considering the diversity of factors that can influence estimates of impact when assessing water scarcity.
| S-EPMC11219772 | biostudies-literature
Project description:BackgroundDuring gene expression analysis by Serial Analysis of Gene Expression (SAGE), duplicate ditags are routinely removed from the data analysis, because they are suspected to stem from artifacts during SAGE library construction. As a consequence, naturally occurring duplicate ditags are also removed from the analysis leading to an error of measurement.ResultsAn algorithm was developed to analyze the differential occurrence of SAGE tags in different ditag combinations. Analysis of a pancreatic acinar cell LongSAGE library showed no sign of a general amplification bias that justified the removal of all duplicate ditags. Extending the analysis to 10 additional LongSAGE libraries showed no justification for removal of all duplicate ditags either. On the contrary, while the error introduced in original SAGE by removal of naturally occurring duplicate ditags is insignificant, it leads to an error of up to 3 fold in LongSAGE. However, the algorithm developed for the analysis of duplicate ditags was able to identify individual artifact ditags that originated from rare nucleotide variations of tags and vector contamination.ConclusionThe removal of all duplicate ditags was unfounded for the datasets analyzed and led to large errors. This may also be the case for other LongSAGE datasets already present in databases. Analysis of the ditag population, however, can identify artifact tags that should be removed from analysis or have their tag count adjusted.
| S-EPMC1839111 | biostudies-literature
Project description:Relating behavioral and neuroimaging measures is essential to understanding human brain function. Often, this is achieved by computing a correlation between behavioral measures, e.g., reaction times, and neurophysiological recordings, e.g., prestimulus EEG alpha-power, on a single-trial-basis. This approach treats individual trials as independent measurements and ignores the fact that data are acquired in a temporal order. It has already been shown that behavioral measures as well as neurophysiological recordings display power-law dynamics, which implies that trials are not in fact independent. Critically, computing the correlation coefficient between two measures exhibiting long-range temporal dependencies may introduce spurious correlations, thus leading to erroneous conclusions about the relationship between brain activity and behavioral measures. Here, we address data-analytic pitfalls which may arise when long-range temporal dependencies in neural as well as behavioral measures are ignored. We quantify the influence of temporal dependencies of neural and behavioral measures on the observed correlations through simulations. Results are further supported in analysis of real EEG data recorded in a simple reaction time task, where the aim is to predict the latency of responses on the basis of prestimulus alpha oscillations. We show that it is possible to "predict" reaction times from one subject on the basis of EEG activity recorded in another subject simply owing to the fact that both measures display power-law dynamics. The same is true when correlating EEG activity obtained from different subjects. A surrogate-data procedure is described which correctly tests for the presence of correlation while controlling for the effect of power-law dynamics.
| S-EPMC6869015 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.pone.0114184.].
| S-EPMC4395350 | biostudies-other
Project description:The hot-hand phenomenon, according to which a player's performance is significantly elevated during certain phases relative to the expected performance based on the player's base rate, has left many researchers and fans in basketball puzzled: The vast majority of players, coaches and fans believe in its existence but statistical evidence supporting this belief has been scarce. It has frequently been argued that the hot hand in basketball is unobservable because of strategic adjustments and defensive interference of the opposing team. We use a dataset with novel metrics, such as the number of defenders and the defensive intensity for each shot attempt, which enable us to directly measure defensive pressure. First, we examine how the shooting percentage of NBA players changes relative to the attributes of each metric. We find that it is of lesser importance by how many defenders a player is guarded but that defensive intensity, e.g., whether a defender raises his hand when his opponent shoots, has a larger impact on shot difficulty. Second, we explore how the underlying metrics and shooting accuracy change as a function of streak length. Our results indicate that defensive pressure and shot difficulty increase (decrease) during hot (cold) streaks, so that defenders seem to behave according to the hot-hand belief and try to force hot players into more difficult shots. However, we find that shooting percentages of presumably hot players do not increase and that shooting performance is not related to streakiness, so that the defenders' hot-hand behavior cannot be considered ecologically rational. Therefore, we are unable to find evidence in favor of the hot-hand effect even when accounting for defensive pressure.
| S-EPMC4256225 | biostudies-literature
Project description:AimsTacrolimus is a cornerstone in modern immunosuppressive therapy after kidney transplantation. Tacrolimus dosing is challenged by considerable pharmacokinetic variability, both between patients and over time after transplantation, partly due to variability in cytochrome P450 3A (CYP3A) activity. The aim of this study was to assess the value of the endogenous CYP3A marker 4β-hydroxycholesterol (4βOHC) for tacrolimus dose individualization early after kidney transplantation.MethodsData were obtained from 79 adult kidney transplant recipients who contributed a total of 625 4βOHC measurements and 1999 tacrolimus whole blood concentrations during the first 2 months after transplantation. The relationships between 4βOHC levels and individual estimates of tacrolimus apparent plasma clearance (CL/Fplasma ) at different time points after transplantation were investigated using scatterplots and population pharmacokinetic modelling.ResultsThere was no significant correlation between pre-transplant 4βOHC levels and tacrolimus CL/Fplasma the first week (r = 0.19 [95% CI -0.03-0.40]) or between 4βOHC and tacrolimus CL/Fplasma 1 week (r = 0.20 [-0.11-0.47]), 4 weeks (r = 0.21 [-0.07-0.46]) or 2 months (r = 0.24 [-0.03-0.48]) after transplantation (P ≥ 0.06). In the population analysis, time-varying 4βOHC was not a statistically significant covariate on tacrolimus CL/Fplasma , neither in terms of absolute values (P = 0.11) nor in terms of changes from baseline (P = 0.17). 4βOHC values increased between 1 week and 2 months after transplantation (median change +57% [IQR +22-83%], P < 0.001), indicating increasing CYP3A activity. Contradictorily, tacrolimus CL/Fplasma decreased over the same period (median change -13% [IQR -3 to -26%], P < 0.001).Conclusions4βOHC does not appear to have a clinical potential to improve individualization of tacrolimus doses early after kidney transplantation.
| S-EPMC5465334 | biostudies-literature
Project description:In biology, organization at multiple scales potentiates biological function. Current advances in staining and imaging of biological tissues provide a wealth of data, but there are few metrics to quantitatively describe these findings. In particular there is a need for a metric that would characterize the correlation and consistency of orientation of different biological constructs within a tissue. We aimed to create such a metric and to demonstrate its use with images of cardiac tissues. The co-orientational order parameter (COOP) was based on the mathematical framework of a classical parameter, the orientational order parameter (OOP). Theorems were proven to illustrate the properties and boundaries of the COOP, which was then applied to both synthetic and experimental data. We showed the COOP to be useful for quantifying the correlation of orientation of constructs such as actin filaments and sarcomeric Z-lines. As expected, cardiac tissues showed perfect correlation between actin filaments and Z-lines. We also demonstrated the use of COOP to quantify the consistency of construct orientation within cells of the same shape. The COOP provides a quantitative tool to characterize tissues beyond co-localization or single construct orientation distribution. In the future, this new parameter could be used to represent the quantitative changes during maturation of cardiac tissue, pathological malformation, and other processes.
| S-EPMC4388480 | biostudies-literature
Project description:High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients' CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A5*3/*3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A5*1. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A5*1 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients' CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.
| S-EPMC8560807 | biostudies-literature