An application programming interface implementing Bayesian approaches for evaluating effect of time-varying treatment with R and Python

IntroductionMethods and tools evaluating treatment effect have been primarily developed for binary type of treatment. Yet, treatment is rarely binary outside the experimental setting, varies by dosage, frequency and time. Treatment is routinely adjusted, initiated or stopped when being administered over a period of time.MethodsBoth Gaussian Process (GP) regression and Bayesian additive regression tree (BART) have been used successfully for handling complex setting involving time-varying treatments that is either adaptive or non-adaptive. Here, we introduce an application programming interface (API) that implements both BART and GP for estimating averaged treatment effect (ATE) and conditional averaged treatment (CATE) for the two-stage time-varying treatment strategies.ResultsWe provide two real applications for evaluating comparative effectiveness of time-varying treatment strategies. The first example evaluates an early aggressive treatment strategies for caring children with newly diagnosed Juvenile Idiopathic Arthritis (JIA). The second evaluates the persistent per-protocol treatment effectiveness in a large randomized pragmatic trial. The examples demonstrate the use of the API calling from R and Python, for handling both non-adaptive or adaptive treatments, with presences of partially observed or missing data issues. Summary tables and interactive figures of the results are downloadable

HIV infection of hepatocytes results in a modest increase in hepatitis C virus expression in vitro.

Previous studies demonstrate that soluble HIV proteins impact both hepatocyte function and HCV replication in vitro. It has also been reported that HIV can productively infect hepatocytes. We therefore investigated the impact of HIV infection of hepatocytes on HCV expression. The Huh7.5JFH1 cell line that constitutively expresses infectious HCV was infected with the lab-adapted strains HIVNL4-3 or HIVYK-JRCSF. HCV expression was quantified via HCV core antigen ELISA, Western blot, and strand-specific real-time PCR for positive-sense and negative-sense HCV RNA. After HIVNL4-3 infection of Huh7.5JFH1 cells, positive-sense and negative-sense HCV RNA levels were elevated compared to HIV uninfected cells. Increased HCV RNA synthesis was also observed after infection of Huh7.5JFH1 cells with HIVYK-JRCSF. HIV-induced HCV core production was decreased in the presence of the anti-HIV drugs AZT, T20, and raltegravir, although these medications had a minimal effect on HCV expression in the absence of HIV. HCV core, NS3, and NS5A protein expression were increased after HIV infection of Huh7.5JFH1 cells. Chemically inactivated HIV had a minimal effect on HCV expression in Huh7.5JFH1 cells suggesting that ongoing viral replication was critical. These data demonstrate that HIV induces HCV RNA synthesis and protein production in vitro and complement previous in vivo reports that HCV RNA levels are elevated in individuals with HIV/HCV co-infection compared to those with HCV mono-infection. These findings suggest that HIV suppression may be a critical factor in controlling liver disease, particularly if the underlying liver disease is not treated

Infection of Huh7.5_JFH1 cells with HIV results in increased HCV core protein production.

<p>100,000 Huh7.5_JFH1 cells were incubated with DNase-treated HIV_NL4-3 at an MOI = 1 for two hours. At days 1, 3, 7, and 14 post-infection, HCV core antigen was quantified in cell lysates in the absence (black bars) or presence (white bars) of HIV. * p≤0.05; ** p≤0.10 compared to HIV-uninfected Huh7.5_JFH1 cells at each time point.</p

HIV infection of Huh7.5_JFH1 cells is inhibited by anti-HIV medications.

<p>100,000 Huh7.5_JFH1 cells were incubated with DNase-treated HIV_NL4-3 (black bars) or HIV_YK-JRCSF (white bars) an MOI = 1 for two hours. Cells were pre-treated with AZT (100 uM), T20 (1 ug/mL), or raltegravir (1–100 nM) for one hour and then during HIV infection and incubation. At day 3 post-infection, HCV core antigen was quantified in cell lysates. * p≤0.05; ** p≤0.10 compared to HIV-uninfected Huh7.5_JFH1 cells under each treatment condition.</p

Infection of Huh7.5_JFH1 cells with HIV results in increased HCV RNA synthesis.

<p>100,000 Huh7.5_JFH1 cells were incubated with DNase-treated HIV_NL4-3 (white bars) or HIV_YK-JRCSF (grey bars) at an MOI = 1 for two hours. At days 1, 3, 7, and 14 post-infection, positive-sense HCV RNA (<b>A</b>) and negative-sense HCV RNA (<b>B</b>) were quantified in cell lysates, compared to the no HIV condition (black bars) by real-time, strand-specific PCR, and normalized to cellular GAPDH levels as described previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083728#pone.0083728-Blackard3" target="_blank">[33]</a>. * p≤0.05; ** p≤0.10 compared to HIV-uninfected Huh7.5_JFH1 cells at each time point.</p

Infection of Huh7.5_JFH1 cells with HIV results in increased HCV NS3 and NS5A protein production.

<p>100,000 Huh7.5_JFH1 cells were incubated with DNase-treated HIV_NL4-3 at an MOI = 1 for two hours. Cell lysates were harvested at days 1, 3, 7, and 14 post-infection for the detection of HCV NS3 and NS5A proteins by Western Blot. Equivalent total cell protein concentrations were loaded, and all data were normalized to cellular GAPDH levels at each time point. The uninfected (no HIV) condition, as well as infection with HIV_NL4-3 in the presence of 100 uM AZT, are shown as additional controls.</p

Chemically inactivated HIV does not increase HCV protein expression.

<p>100,000 Huh7.5_JFH1 cells were incubated with infectious HIV_NL4-3 alone, infectious HIV_NL4-3 + 100 uM AZT, no HIV, or AT-2-treated HIV_NL4-3 (50 ng, 100 ng, or 200 ng) at an MOI = 1 for two hours. At days 1 and 3 post-infection, HCV core antigen was quantified in cell lysates (white bars) and culture supernatants (black bars). * p≤0.05; ** p≤0.10 compared to HIV-uninfected Huh7.5_JFH1 cells at each time point. Arrows highlight the control – no infectious HIV added – condition.</p

Differential Effect of Fixed Ratio Magnitude on the Rate of Lever-Pressing and Interinjection Intervals of Cocaine Self-Administration in Rats

ABSTRACT: Background: Many features of self-administration behavior may be explained by reference to the properties of schedules of reinforcement. Schedules alter the probability of a behavior being reinforced and thereby increase, or decrease, the frequency of the behavior and fixed ratio (FR) magnitude reportedly alters the rate of responding to cocaine. A pharmacokinetic/pharmacodynamic interaction theory states that lever-pressing behavior is induced only when cocaine levels in the body are above the priming/remission threshold and below the satiety threshold—a range termed the compulsion zone. This theory successfully explains cocaine self-administration in rats on a progressive ratio and the FR1 schedule. Objectives: To determine the effects of high FR magnitude on the rate of self-administration of cocaine and the rate of lever-pressing behavior when cocaine levels are within the compulsion zone. Methods: Rats acquired cocaine self-administration on an FR1 schedule and then were switched to sessions that started with FR1 and then FR 5, 10, 20, or 50. An only FR1 session was run each week between FR1/FR50 sessions and then only FR1 sessions were conducted for several weeks. Results: Interinjection intervals at a unit dose of 3 µmol/kg were regular at both FR1 and FR50 but were longer by the time required to complete the 50 presses. When responding by rats was maintained under an FR50 schedule of cocaine presentations, compared to baseline FR1 sessions, dramatic increases in the number of lever-presses were observed after access to cocaine was terminated, a previously unreported finding. However, lever-pressing occurred only when cocaine levels were in the compulsion zone, and this duration was unchanged. The increase in lever-pressing persisted for weeks. Interinjection intervals at FR1 were not altered after exposure to FR50. Conclusions: Although previously considered key to understanding the regulation of cocaine self-administration behavior, FR magnitude simply increased interinjection intervals by the time required to complete 50 lever-presses. The dramatic increase in the rate of lever-pressing was caused by the high FR schedule rather than cocaine. The utility of the schedule-induced increase in the rate of lever-pressing is unclear. The compulsion zone theory provides a rational pharmacological basis for understanding cocaine self-administration behavior