diff --git a/Paper/.gitignore b/Paper/.gitignore new file mode 100644 index 0000000..be86fef --- /dev/null +++ b/Paper/.gitignore @@ -0,0 +1,5 @@ +*.pdf +*.aux +*.lof +*.lot +*.idx diff --git a/Paper/Main.tex b/Paper/Main.tex index 4149e61..79b47bf 100644 --- a/Paper/Main.tex +++ b/Paper/Main.tex @@ -68,10 +68,10 @@ Section \ref{SEC:Results} discusses the results of the analysis. \subfile{sections/10_CausalStory} \subfile{sections/02_data} -%--------------------------------------------------------------- -\section{Causal Identification}\label{SEC:CausalIdentification} -%--------------------------------------------------------------- -\subfile{sections/03_CausalIdentification} +% %--------------------------------------------------------------- +% \section{Causal Identification}\label{SEC:CausalIdentification} +% %--------------------------------------------------------------- +% \subfile{sections/03_CausalIdentification} %--------------------------------------------------------------- \section{Econometric Model}\label{SEC:EconometricModel} @@ -103,6 +103,7 @@ Section \ref{SEC:Results} discusses the results of the analysis. %--------------------------------------------------------------- \section{Appendicies} %--------------------------------------------------------------- +\subfile{sections/21_appendix_diagnostics} \newpage \tableofcontents diff --git a/Paper/jmp_layout.kdl b/Paper/jmp_layout.kdl index 1cbc57d..b9ecab0 100644 --- a/Paper/jmp_layout.kdl +++ b/Paper/jmp_layout.kdl @@ -1,5 +1,5 @@ layout { - tab name="Main and Compile" cwd="~/research/PhD_Deliverables/jmp/Latex/Paper/" hide_floating_panes=true focus=true { + tab name="Main and Compile" cwd="./" hide_floating_panes=true focus=true { // This tab is where I manage main from. // it opens up Main.txt for my JMP, opens the pdf in okular (in a floating tab), and then get's ready to build the pdf. pane size=1 borderless=true { @@ -33,7 +33,7 @@ layout { } } - tab name="sections" cwd="~/research/PhD_Deliverables/jmp/Latex/Paper/sections/" { + tab name="sections" cwd="sections/" { pane size=1 borderless=true { plugin location="tab-bar" } @@ -56,7 +56,7 @@ layout { } } - tab name="git" cwd="~/research/PhD_Deliverables/jmp/Latex/Paper/" { + tab name="git" cwd="./" { pane size=1 borderless=true { plugin location="tab-bar" } @@ -73,7 +73,7 @@ layout { } pane command="git" { - args "log" "-n 10" "--all" "--oneline" "--graph" "--stat" "--decorate" + args "log" "--all" "--oneline" "--graph" "--stat" "--decorate" } } diff --git a/Paper/sections/04_EconometricModel.tex b/Paper/sections/04_EconometricModel.tex index b8f2d6c..b792f3f 100644 --- a/Paper/sections/04_EconometricModel.tex +++ b/Paper/sections/04_EconometricModel.tex @@ -3,66 +3,133 @@ \begin{document} %% Describe goal -% Estimate probability distribution of normalized durations and conclusion statuses. -% Explain why this answers questions well. -% How do I propose estimating that? +The model I use is a +hierarchal logistic regression model where the +hierarchies are based on disease categories. %%NOTATION +% change notation +% i indexes trials for y and d +% n indexes snapshots within the trial First, some notation: \begin{itemize} + \item $i$: indexes trials \item $n$: indexes trial snapshots. - \item $y_n$: whether each trial terminated (true) or completed (false). - \item $d$: indexes ICD-10 disease categories. - \item $d_n$: represents the disease category of the trial associated with the snapshot $n$. - \item $x_n$: represents the other dependent variables associated to the snapshot. - This includes\footnote{No trials in the current dataset are ever suspended.}: - \begin{enumerate} - \item Elapsed duration - \item arcsinh of the number of brands - \item arcsinh of the DALYs from high SDI countries - \item arcsinh of the DALYs from high-medium SDI countries - \item Enrollment (no distinction between anticipated or actual) - \item Dummy Status: Not yet recruiting - \item Dummy Status: Recruiting - \item Dummy Status: Active, not recruiting - \item Dummy Status: Enrolling by invitation - \end{enumerate} + \item $y_i$: whether each trial + terminated (true, 1) or completed (false, 0). + \item $d_i$: indexes the ICD-10 disease category of the trial. + \item $x_{i,n}$: represents the independent + variables associated with the snapshot. \end{itemize} -The arcsinh transform is used because it is similar to a log transform but -maps $\text{arcsinh}(0)=0$. - -The bayesian model to measure the direct effects of enrollment and the number -of other brands is easily specified as a hierarchal logistic regression. +The goal is to take each snapshot and predict +The actual specification of the model to measure +the direct effect of enrollment is: \begin{align} - y_n \sim \text{Bernoulli}(p_n) \\ - p_n = \text{logit}(x_n \vec \beta(d_n)) + y_i \sim \text{Bernoulli}(p_{i,n}) \\ + p_{i,n} = \text{logit}(x_{i,n} \vec \beta(d_i)) \end{align} -Where beta is indexed by $k$ for each parameter in $x$, and by -$d \in \{1,2,\dots,21,22\}$ for each general ICD-10 category. +Where beta is indexed by +$d \in \{1,2,\dots,21,22\}$ +for each general ICD-10 category. The betas are distributed \begin{align} - \beta_k(d) \sim \text{Normal}(\mu_k,\sigma_k) + \beta(d_i) \sim \text{Normal}(\mu_i,\sigma_i I) \end{align} -With hyperparameters +With hyperpriors +%Checked on 2024-11-27. Is corrrect. \todo{Double check that these are the priors I used.} \begin{align} \mu_k \sim \text{Normal}(0,0.05) \\ \sigma_k \sim \text{Gamma}(4,20) \end{align} +\todo{Double check actual spec} -Other variables are implicitly conditioned on as they were used -to select trials of interest. +The independent variables include: +\todo{Make sure data is described before this point.} +\begin{subequations} +\begin{align} + x_{i,n}\beta(d_i) + = & \bx{1}{\text{Elapsed Duration}} \\ + &+ \bx{2}{\arcsinh \left(\text{\# Generic compunds}\right)} \\ + &+ \bx{3}{\arcsinh \left(\text{\# Branded compunds}\right)} \\ + &+ \bx{4}{\text{\# DALYs in High SDI Countries}} \\ + &+ \bx{5}{\text{\# DALYs in High-Medium SDI Countries}} \\ + &+ \bx{6}{\text{\# DALYs in Medium SDI Countries}} \\ + &+ \bx{7}{\text{\# DALYs in Low-Medium SDI Countries}} \\ + &+ \bx{8}{\text{\# DALYs in Low SDI Countries}} \\ + &+ \bxi{9}{\text{Not yet Recruiting}}{\text{Trial Status}}\\ + &+ \bxi{10}{\text{Recruiting}}{\text{Trial Status}}\\ + &+ \bxi{11}{\text{Enrolling by Invitation Only}}{\text{Trial Status}}\\ + &+ \bxi{12}{\text{Active, not recruiting}}{\text{Trial Status}} +\end{align} +\end{subequations} +The arcsinh transform is used because it is similar to a log transform but +differentiably handles counts of zero since +$\text{arcsinh}(0) = \ln (0 + \sqrt{0^2 + 1}) =0$. +Note that in this is a heirarchal model, each IDC-10 disease category +gets it's own set of parameters, and that is why the $\beta$s are parameterized +by $d_i$. +%%%% Not sure if space should go here. I think these work well together. +Other variables are implicitly controlled for as they are used +to select the trials of interest. These include: + \todo{double check these in the code.} \begin{itemize} - \item Is the trial Phase 3?\footnote{ - Conditioning on phase 3 is equivalent to asserting that previous trials - occured and had acceptable safety and efficacy results. - } - \item Does the trial have a Data Monitoring Committee? - \item Are the compounds an FDA regulated drug? + \item The trial is Phase 3. + \item The trial has a Data Monitoring Committee. + \item The compounds are FDA regulated drug. + \item The trial was never suspended\footnote{ + This was because I wasn't sure how to handle it in the model + when I started scraping the data. + Later the website changed. + This is technically post selection. + \todo{double check where this happened in the code. + I may have only done it in the CBO analysis.} + } \end{itemize} -%TODO: double check the sql used to select trials of interest. + +\subsection{Interpretation} +% Explain +% - What do we care about? Changes in the probability of +% - distribution of differences -> relate to E(\delta Y) +% - How do we obtain this distribution of differences? +% - from the model, we pay attention to P under treatment and control +% - We obtain this by fitting the model, then simulating under treatment and control, and taking the difference in the probability. +% - + +The specific measure of interest is how much a delay in +closing enrollment changes the probability of terminating a trial +$p_{i,n}$ in the model. + +In the standard reduced form causal inference, the treatment effect +of interest for outcome $Z$ is measured as +\begin{align} + E(Z(\text{Treatment}) - Z(\text{Control})) + = E(Z(\text{Treatment})) - E(Z(\text{Control})) +\end{align} +Because $Z(\text{Treatment})$ and $Z(\text{Control})$ are random variables, +$Z(\text{Treatment}) - Z(\text{Control}) = \delta_Z$, is also a random variable. +In the bayesian framework, this parameter has a distribution, and so +we can calculate the distribution of differences in +the probability of termination due to a given delay in +closing recrutiment, +$p_{i,n}(T) - p_{i,n}(C) = \delta_{p_{i,n}}$. + +I calculate the posterior distribution of $\delta_{p_{i,n}}$ by estimating the +posterior distributions of the $\beta$s and then simulating $\delta_{p_{i,n}}$. +This involves taking a draw from the $\beta$s distribution, calculating +$p_{i,n}(C)$ +for the underlying trials at the snapshot when they close enrollment +and then calculating +$p_{i,n}(T)$ +under the counterfactual where enrollment had not yet closed. +The difference +$\delta_{p_{i,n}}$ +is then calculated for each trial, and saved. +After repeating this for all the posterior samples, we have an esitmate +for the posterior distribution of differences between treatement and control. + \end{document} diff --git a/Paper/sections/06_Results.tex b/Paper/sections/06_Results.tex index 999e056..bf4a34e 100644 --- a/Paper/sections/06_Results.tex +++ b/Paper/sections/06_Results.tex @@ -1,119 +1,206 @@ \documentclass[../Main.tex]{subfiles} \begin{document} -%\subsection{Data Exploration} %TODO: fill this out later. -%look at trial -\subsection{Model Fitting} -In this section we examine the results from fitting the econometric model using -mc-stan (\cite{mc-stan}) through the rstan (\cite{rstan}) interface. - -%describe -The model was based on the hierarchal logistic regression model -presented in the Stan Users Guide (\cite{mc-stan}), -and was run with 2,500 warmup iterations and -2,500 sampling iterations in six chains. -There were various issues, including 160 divergent transitions and the R-hat -measure was 1.49. -Overall these suggest that the econometric model is incorrect as -written or requires reparameterization. -%TODO: and info about how I learned about these diagnostics - - -% \subsubsection{Diagnostics} -% %Examine trank plots -% To identify which parameters were problematic, I first looked at trace rank -% histograms. -% Under idea circumstances, each line (representing a chain) should exchange -% places with the other lines frequently. -% In both \cref{fig:mu_trank} and \cref{fig:sigma_trank}, most parameters seem -% to mix well but there are a couple of exceptions. -% This warrants further investigation. -% -% \begin{figure}[H] -% \includegraphics[width=\textwidth]{../assets/img/mu_trank.png} -% \caption{Trace Rank Histogram: Mu values} -% \label{fig:mu_trank} -% \end{figure} -% -% \begin{figure}[H] -% \includegraphics[width=\textwidth]{../assets/img/sigma_trank.png} -% \caption{Trace Rank Histogram: Sigma values} -% \label{fig:sigma_trank} -% \end{figure} -% -% %Take a look at batman and points for mu -% In the case of the Mu values, a parallel coordinates plot -% doesn't seem to indicate any parameters as likely candidates -% for causing the issues with divergent transitions. -% \begin{figure}[H] -% \includegraphics[width=\textwidth]{../assets/img/mu_batman.png} -% \caption{Parallel Coordinate Plot: Mu values} -% \label{fig:mu_batman} -% \end{figure} -% Note that at each parameter, there is some level of dispersion between -% values that diverged. -% -% On the other hand, in the parallel coordinates plot for sigma values, -% it appears that most divergent transitions occur with values of -% sigma[1], sigma[3], sigma[6], and sigma[7] close to zero. -% \begin{figure}[H] -% \includegraphics[width=\textwidth]{../assets/img/sigma_batman.png} -% \caption{Parallel Coordinate Plot: Sigma values} -% \label{fig:sigma_batman} -% \end{figure} -% Overall this suggests that there is an issue with the specification -% of the covariance structures of the hyperparameters. -% -% Additional evidence that the covariance structure is incorrect comes from -% plotting pairs of parameter values and examining the chains with divergent -% transitions. -% -% \begin{figure}[H] -% \includegraphics[width=\textwidth]{../assets/img/sigma_pairs_5-9.png} -% \caption{Parameter Pairs plots: Sigma[5] through Sigma[9]} -% \label{fig:sigma_pairs_5-9.png} -% \end{figure} -% From this we can see that divergent pairs are highly correlated with the cases -% where sigma[6] or sigma[7] are equal to zero. -% This has an impact on the shape of both of those estimated parameters, causing -% both to be bimodal. - - -\subsection{Interpretation} - -The key results so far are related to the distribution of differences in $p$. - -In figure \ref{fig:pred_dist_dif_delay} we see that there while most trials do not see any increased risk -from a delay in closing enrollment, there is a small group that does experience this. + +In this section +I describe the model fitting, the posteriors of the parameters of interest, +and intepret the results. + + +\subsection{Data Summaries and Estimation Procedure} + +% Data Summaries +Overall, I successfully processed 162 trials, with 1,347 snapshots between them. +Figure \ref{fig:snapshot_counts} shows the histogram of snapshots per trial. +Most trials lasted less than 1,500 days, as can be seen in +\ref{fig:trial_durations}. +Although there are a large number of snapshots that will be used to fit the +model, the number of trials -- the unit of observation -- are quite low. +Add to the fact that these are spread over multiple ICD-10 categories +and the overall quantity of trials is quite low. + +To continue, we can use a scatterplot to get a rough idea of the observed +relationship between the number of snapshots and the duration of trials. +We can see this in Figure \ref{fig:snapshot_duration_scatter}, where +the correlation (measured at $0.34$) is apparent. + \begin{figure}[H] - \includegraphics[width=\textwidth]{../assets/img/current/pred_dist_diff-delay} - \caption{} - \label{fig:pred_dist_diff_delay} + \includegraphics[width=\textwidth]{../assets/img/trials_details/HistTrialDurations_Faceted} + \todo{Replace this graphic with the histogram of trial durations} + \caption{Histograms of Trial Durations} + \label{fig:trial_durations} \end{figure} -Figure \ref{fig:pred_dist_dif_delay2} shows how this varies across disease categories \begin{figure}[H] - \includegraphics[width=\textwidth]{../assets/img/current/pred_dist_diff-delay-group} - \caption{} - \label{fig:pred_dist_dif_delay2} + \includegraphics[width=\textwidth]{../assets/img/trials_details/HistSnapshots} + \todo{Replace this graphic with the histogram of snapshots} + \caption{Histogram of the count of Snapshots} + \label{fig:snapshot_counts} \end{figure} -We can also examine the direct effect from adding a single generic competitior drug. +\begin{figure}[H] + \includegraphics[width=\textwidth]{../assets/img/trials_details/SnapshotsVsDurationVsTermination} + \todo{Replace this graphic with the scatterplot comparing durations and snapshots} + \caption{Scatterplot comparing the Count of Snapshots and Trial Duration} + \label{fig:snapshot_counts} +\end{figure} + +% Estimation Procedure +I fit the econometric model using mc-stan +\cite{standevelopmentteam_StanModelling_2022} +through the rstan +\cite{standevelopmentteam_RStanInterface_2023} +interface using 4 chains with +%describe +2,500 +warmup iterations and +2,500 +sampling iterations each. + +Two of the chains experienced a low +Estimated Baysian Fraction of Missing Information (E-BFMI) , +suggesting that there are some parts of the posterior distribution +that were not explored well during the model fitting. +I presume this is due to the low number of trials in some of the +ICD-10 categories. +We can see in Figure \ref{fig:barchart_idc_categories} that some of these +disease categories had a single trial represented while others were +not represented at all. \begin{figure}[H] - \includegraphics[width=\textwidth]{../assets/img/current/pred_dist_diff-generic} - \caption{} - \label{fig:pred_dist_diff_generic} + \includegraphics[width=\textwidth]{../assets/img/trials_details/CategoryCounts} + \caption{Bar chart of trials by ICD-10 categories} + \label{fig:barchart_idc_categories} \end{figure} -Figure \ref{fig:pred_dist_dif_generic2} shows how this varies across disease categories + +\subsection{Primary Results} + +The primary, causally-identified value we can estimate is the change in +the probability of termination caused by (counterfactually) keeping enrollment +open instead of closing enrollment when observed. +In figure \ref{fig:pred_dist_diff_delay} below, we see this impact of +keeping enrollment open. + + +\begin{figure}[H] + \includegraphics[width=\textwidth]{../assets/img/dist_diff_analysis/p_delay_intervention_distdiff_boxplot} + \todo{Replace this graphic with the histdiff with boxplot} + \small{ + Values near 1 indicate a near perfect increase in the probability + of termination. + Values near 0 indicate little change in probability, + while values near -1, represent a decrease in the probability + of termination. + The scale is in probability points, thus a value near 1 is a change + from unlikely to terminate under control, to highly likely to + terminate. + } + \caption{Histogram of the Distribution of Predicted Differences} + \label{fig:pred_dist_diff_delay} +\end{figure} + +There are a few interesting things to point out here. +Let's start by getting aquainted with the details of the distribution above. +% - spike at 0 +% - the boxplot +% - 63% of mass below 0 : find better way to say that +% - For a random trial, there is a 63% chance that the impact is to reduce the probability of a termination. +% - 2 pctg-point wide band centered on 0 has ~13% of the masss +% - mean represents 9.x% increase in probability of termination. A quick simulation gives about the same pctg-point increase in terminated trials. + +A few interesting interpretation bits come out of this. +% - there are 3 regimes: low impact (near zero), medium impact (concentrated in decreased probability of termination), and high impact (concentrated in increased probability of termination). +The first this that there appear to be three different regimes. +The first regime consists of the low impact results, i.e. those values of $\delta_p$ +near zero. +About 13\% of trials lie within a single percentage point change of zero, +suggesting that there is a reasonable chance that delaying +a close of enrollment has no impact. +The second regime consists of the moderate impact on clinical trials' +probabilities of termination, say values in the interval $[-0.5, 0.5]$ +on the graph. +Most of this probability mass is represents a decrease in the probability of +a termination, some of it rather large. +Finally, there exists the high impact region, almost exclusively concentrated +around increases in the probability of termination at $\delta_p > 0.75$. +These represent cases where delaying the close of enrollemnt changes a trial +from a case where they were highly likely to complete their primary objectives to +a case where they were likely or almost certain to terminate the trial early. +% - the high impact regime is strange because it consists of trials that moved from unlikely (<20% chance) of termination to a high chance (>80% chance) of termination. Something like 5% of all trials have a greater than 98 percentage point increase in termination. Not sure what this is doing. + +% - Potential Explanations for high impact regime: +How could this intervention have such a wide range in the intensity +and direction of impacts? +A few explanations include that some trials are suceptable or that this is a +result of too little data. +% - Some trials are highly suceptable. This is the face value effect +One option is that some categories are more suceptable to +issues with participant enrollment. +If this is the case, we should be able to isolate categories that contribute +the most to this effect. +Another is that this might be a modelling artefact, due to the relatively +low number of trials in certain ICD-10 categories. +In short, there might be high levels of uncertanty in some parameter values, +which manifest as fat tails in the distributions of the $\beta$ parameters. +Because of the logistic format of the model, these fat tails lead to +extreme values of $p$, and potentally large changes $\delta_p$. +% - Could be uncertanty. If the model is highly uncertain, e.g. there isn't enough data, we could have a small percentage of large increases. This could be in general or just for a few categories with low amounts of data. +% - +% - + +I believe that this second explanation -- a model artifact due to uncertanty -- +is likely to be the cause. +Three points lead me to believe this: +\begin{itemize} + \item The low fractions of E-BFMI suggest that the sampler is struggling + to explore some regions of the posterior. + According to \cite{standevelopmentteam_RuntimeWarnings_2022} this is + often due to thick tails of posterior distributions. + \item When we examine the results across different ICD-10 groups, + \ref{fig:pred_dist_dif_delay2} + \todo{move figure from below} + we note this same issue. + \item In Figure \ref{fig:betas_delay}, we see that some some ICD-10 categories + \todo{add figure} + have \todo{note fat tails}. + \item There are few trials available, particularly among some specific + ICD-10 categories. +\end{itemize} +% - take a look at beta values and then discuss if that lines up with results from dist-diff by group. +% - My initial thought is that there is not enough data/too uncertain. I think this because it happens for most/all of the categories. +% - +% - +% - +Overally it is hard to escape the conclusion that more data is needed across +many -- if not all -- of the disease categories. + + + +Figure \ref{fig:pred_dist_dif_delay2} shows how this overall +result comes from different disease categories. \begin{figure}[H] - \includegraphics[width=\textwidth]{../assets/img/current/pred_dist_diff-generic-group} - \caption{} - \label{fig:pred_dist_dif_generic2} + \includegraphics[width=\textwidth]{../assets/img/dist_diff_analysis/p_delay_intervention_distdiff_by_group} + \caption{Distribution of Predicted differences by Disease Group} + \label{fig:pred_dist_dif_delay2} \end{figure} +\subsection{Secondary Results} + +% Examine beta parameters +% - Little movement except where data is strong, general negative movement. Still really wide +% - Note how they all learned (partial pooling) reduction in \beta from ANR? +% - Need to discuss the 5 different states. Can't remember which one is dropped for the life of me. May need to fix parameterization. +% - + +\begin{figure}[H] + \includegraphics[width=\textwidth]{../assets/img/betas/parameter_across_groups/parameters_12_status_ANR} + \caption{Distribution of parameters associated with ``Active, not recruiting'' status, by ICD-10 Category} + \label{fig:parameters_ANR_by_group} +\end{figure} +% - + \end{document} diff --git a/Paper/sections/08_PotentialImprovements.tex b/Paper/sections/08_PotentialImprovements.tex index 2f89ab3..c85cae7 100644 --- a/Paper/sections/08_PotentialImprovements.tex +++ b/Paper/sections/08_PotentialImprovements.tex @@ -12,40 +12,40 @@ The most important step is to increase the number of observations available. Currently this requires matching trials to ICD-10 codes by hand, but there are certainly some steps that can be taken to improve the speed with which this can be done. - -\subsection{Covariance Structure} - -As noted in the diagnostics section, many of the convergence issues seem -to occure in the covariance structure. -Instead of representing the parameters $\beta$ as independently normal: -\begin{align} - \beta_k(d) \sim \text{Normal}(\mu_k, \sigma_k) -\end{align} -I propose using a multivariate normal distribution: -\begin{align} - \beta(d) \sim \text{MvNormal}(\mu, \Sigma) -\end{align} -I am not familiar with typical approaches to priors on the covariance matrix, -so this will require a further literature search as to best practices. - -\subsection{Finding Reasonable Priors} - -In standard bayesian regression, heavy tailed priors are common. -When working with a bayesian bernoulli-logit model, this is not appropriate as -heavy tails cause the estimated probabilities $p_n$ to concentrate around the -values $0$ and $1$, and away from values such as $\frac{1}{2}$ as discussed in -\cite{mcelreath_statistical_2020}. %TODO: double check the chapter for this. - -I indend to take the general approach recommended in \cite{mcelreath_statistical_2020} of using -prior predictive checks to evaluate the implications of different priors -on the distribution on $p_n$. -This would consist of taking the independent variables and predicting the values -of $p_n$ based on a proposed set of priors. -By plotting these predictions, I can ensure that the specific parameter priors -used are consistent with my prior beliefs on how $p_n$ behaves. -Currently I believe that $p_n$ should be roughly uniform or unimodal, centered -around $p_n = \frac{1}{2}$. - +% +% \subsection{Covariance Structure} +% +% As noted in the diagnostics section, many of the convergence issues seem +% to occure in the covariance structure. +% Instead of representing the parameters $\beta$ as independently normal: +% \begin{align} +% \beta_k(d) \sim \text{Normal}(\mu_k, \sigma_k) +% \end{align} +% I propose using a multivariate normal distribution: +% \begin{align} +% \beta(d) \sim \text{MvNormal}(\mu, \Sigma) +% \end{align} +% I am not familiar with typical approaches to priors on the covariance matrix, +% so this will require a further literature search as to best practices. + +% \subsection{Finding Reasonable Priors} +% +% In standard bayesian regression, heavy tailed priors are common. +% When working with a bayesian bernoulli-logit model, this is not appropriate as +% heavy tails cause the estimated probabilities $p_n$ to concentrate around the +% values $0$ and $1$, and away from values such as $\frac{1}{2}$ as discussed in +% \cite{mcelreath_statistical_2020}. %TODO: double check the chapter for this. +% +% I indend to take the general approach recommended in \cite{mcelreath_statistical_2020} of using +% prior predictive checks to evaluate the implications of different priors +% on the distribution on $p_n$. +% This would consist of taking the independent variables and predicting the values +% of $p_n$ based on a proposed set of priors. +% By plotting these predictions, I can ensure that the specific parameter priors +% used are consistent with my prior beliefs on how $p_n$ behaves. +% Currently I believe that $p_n$ should be roughly uniform or unimodal, centered +% around $p_n = \frac{1}{2}$. +% \subsection{Imputing Enrollment} @@ -81,21 +81,17 @@ found a way to do so. \subsection{Improving Measures of Market Conditions} -Finally, the currently employed measure of market conditions -- the number of -brands using the same active ingredients -- is not a very good measure of -the options available to potential participants of a clinical trial. -The ideal measures would capture the alternatives available to treat a given -disease (drug meeting the given indication) at the time of the trial snapshot, -but this data is hard to come by. In addition to the fact that many diseases may be treated by non-pharmaceutical means, off-label prescription of pharmaceuticals is legal at the federal level (\cite{commissioner_understanding_2019}). These two facts both complicate measuring market conditions. - -One dataset that I have only investigated briefly is the \url{DrugCentral.org} -database which tracks official indications and some off-label indications as -well -(\cite{ursu_drugcentral_2017}). +One way to address non-pharmaceutical treatments is to concentrate on domains +that are primarily treated by pharmaceuticals. +This requires domain knowledge that I don't have. +% One dataset that I have only investigated briefly is the \url{DrugCentral.org} +% database which tracks official indications and some off-label indications as +% well +% (\cite{ursu_drugcentral_2017}). \end{document} diff --git a/Paper/sections/10_CausalStory.tex b/Paper/sections/10_CausalStory.tex index 331f4f1..5ce5883 100644 --- a/Paper/sections/10_CausalStory.tex +++ b/Paper/sections/10_CausalStory.tex @@ -69,7 +69,7 @@ in the first place while currently observed safety and efficiency results help the sponsor judge whether or not to continue the trial. %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% -\subsection{Clinical Trials Data Sources} +\subsection{Data Summary} %% Describe data here Since Sep 27th, 2007 those who conduct clinical trials of FDA controlled drugs or devices on human subjects must register diff --git a/Paper/sections/12_clinical_trial_background.tex b/Paper/sections/12_clinical_trial_background.tex index fe16b8f..7016d35 100644 --- a/Paper/sections/12_clinical_trial_background.tex +++ b/Paper/sections/12_clinical_trial_background.tex @@ -58,10 +58,29 @@ purpose of the clinical trials process. On the other hand, when a trial terminates early due to reasons other than safety or efficacy concerns, the trial operator does not learn if the drug is effective or safe. -This is a true failure in that we did not learn if the drug was effective or not. -Unfortunately, although termination documentation typically includes a -description of a reason for the clinical trial termination, this doesn't necessarily -list all the reasons contributing to the trial termination and may not exist for a given trial. +This is a knowledge-gathering failure where the trial operator +did not learn if the drug was effective or not. +I prefer describing a clinical trial as being terminated for +\begin{itemize} + \item Safety or Efficacy concerns + \item Strategic concerns + \item Operational concerns. +\end{itemize} + +Unfortunately it can be difficult to know why a given trial was terminated, +in spite of the fact that upon termination, trials typically record a +description of \textit{a single} reason for the clinical trial termination. +This doesn't necessarily list all the reasons contributing to the trial termination and may not exist for a given trial. +For example, if a Principle Investigator leaves for another institution +(terminating the trial), is this decison affected by +a safety or efficacy concern, +a new competitor on the market, +difficulting recruiting participants, +or a lack of financial support from the study sponsor? +Estimating the impact of different problems that trials face from these +low-information, post-hoc signals is insufficient. +For this reason, I use clinical trial progression to estimate effects. +\todo{not sure if this is the best place for this.} As a trial goes through the different stages of recruitment, the investigators update the records on ClinicalTrials.gov. diff --git a/Paper/sections/21_appendix_diagnostics.tex b/Paper/sections/21_appendix_diagnostics.tex new file mode 100644 index 0000000..848b484 --- /dev/null +++ b/Paper/sections/21_appendix_diagnostics.tex @@ -0,0 +1,38 @@ +\documentclass[../Main.tex]{subfiles} +\graphicspath{{\subfix{Assets/img/}}} + +\begin{document} +\subsection{Diagnostics} +Reported low E-BFMI scores (low is considered below $0.2$) +\todo{Fill these out based on what is in the rendered report.} +\begin{itemize} + \item Chain 1: 0.178 + \item Chain 2: 0.189 +\end{itemize} + +No other reported issues. + +\begin{figure}[H] + \caption{Diagnostics: Trace Rank Plots - $\mu$} + \label{fig:trial_durations} + \includegraphics[width=\textwidth]{../assets/img/diagnostics/trace_rank_plot_mu_1-4} + \\[\smallskipamount] + \includegraphics[width=\textwidth]{../assets/img/diagnostics/trace_rank_plot_mu_5-8} + \\[\smallskipamount] + \includegraphics[width=\textwidth]{../assets/img/diagnostics/trace_rank_plot_mu_9-12} +\end{figure} +Mixing seems to be fine + +\begin{figure}[H] + \caption{Diagnostics: Trace Rank Plots - $\sigma$} + \label{fig:trial_durations} + \includegraphics[width=\textwidth]{../assets/img/diagnostics/trace_rank_plot_sigma_1-4} + \\[\smallskipamount] + \includegraphics[width=\textwidth]{../assets/img/diagnostics/trace_rank_plot_sigma_5-8} + \\[\smallskipamount] + \includegraphics[width=\textwidth]{../assets/img/diagnostics/trace_rank_plot_sigma_9-12} +\end{figure} +Mixing is slower than $\mu$ values, but doesn't seem too problematic in light of +other deficencies such as low number of observations. + +\end{document} diff --git a/assets/img/Images/CategoryCounts.png b/assets/img/Images/CategoryCounts.png deleted file mode 100644 index 8e12331..0000000 Binary files a/assets/img/Images/CategoryCounts.png and /dev/null differ diff --git a/assets/img/Images/DirectEffects/Parameters/01_elapsed_duration.png b/assets/img/Images/DirectEffects/Parameters/01_elapsed_duration.png deleted file mode 100644 index 39e4476..0000000 Binary files a/assets/img/Images/DirectEffects/Parameters/01_elapsed_duration.png and /dev/null differ diff 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