# Evaluation of Surrogate Endpoints in Clinical Trials

## Documentation for package ‘Surrogate’ version 2.0

- DESCRIPTION file.
- Package NEWS.

## Help Pages

A B C E F I L M O P R S T U

## -- A --

AA.MultS | Compute the multiple-surrogate adjusted association
ARMD | Data of the Age-Related Macular Degeneration Study
ARMD.MultS | Data of the Age-Related Macular Degeneration Study with multiple candidate surrogates

## -- B --

BifixedContCont | Fits a bivariate fixed-effects model to assess surrogacy in the meta-analytic multiple-trial setting (Continuous-continuous case)
BimixedCbCContCont | Fits a bivariate mixed-effects model using the cluster-by-cluster (CbC) estimator to assess surrogacy in the meta-analytic multiple-trial setting (Continuous-continuous case)
BimixedContCont | Fits a bivariate mixed-effects model to assess surrogacy in the meta-analytic multiple-trial setting (Continuous-continuous case)
Bootstrap.MEP.BinBin | Bootstrap 95% CI around the maximum-entropy ICA and SPF (surrogate predictive function)

## -- C --

CausalDiagramBinBin | Draws a causal diagram depicting the median informational coefficients of correlation (or odds ratios) between the counterfactuals for a specified range of values of the ICA in the binary-binary setting.
CausalDiagramContCont | Draws a causal diagram depicting the median correlations between the counterfactuals for a specified range of values of ICA or MICA in the continuous-continuous setting
comb27.BinBin | Assesses the surrogate predictive value of each of the 27 prediction functions in the setting where both S and T are binary endpoints

## -- E --

ECT | Apply the Entropy Concentration Theorem

## -- F --

Fano.BinBin | Evaluate the possibility of finding a good surrogate in the setting where both S and T are binary endpoints
FixedBinBinIT | Fits (univariate) fixed-effect models to assess surrogacy in the binary-binary case based on the Information-Theoretic framework
FixedBinContIT | Fits (univariate) fixed-effect models to assess surrogacy in the case where the true endpoint is binary and the surrogate endpoint is continuous (based on the Information-Theoretic framework)
FixedContBinIT | Fits (univariate) fixed-effect models to assess surrogacy in the case where the true endpoint is continuous and the surrogate endpoint is binary (based on the Information-Theoretic framework)
FixedContContIT | Fits (univariate) fixed-effect models to assess surrogacy in the continuous-continuous case based on the Information-Theoretic framework
FixedDiscrDiscrIT | Investigates surrogacy for binary or ordinal outcomes using the Information Theoretic framework

## -- I --

ICA.BinBin | Assess surrogacy in the causal-inference single-trial setting in the binary-binary case
ICA.BinBin.CounterAssum | ICA (binary-binary setting) that is obtaied when the counterfactual correlations are assumed to fall within some prespecified ranges.
ICA.BinBin.Grid.Full | Assess surrogacy in the causal-inference single-trial setting in the binary-binary case when monotonicity for S and T is assumed using the full grid-based approach
ICA.BinBin.Grid.Sample | Assess surrogacy in the causal-inference single-trial setting in the binary-binary case when monotonicity for S and T is assumed using the grid-based sample approach
ICA.BinBin.Grid.Sample.Uncert | Assess surrogacy in the causal-inference single-trial setting in the binary-binary case when monotonicity for S and T is assumed using the grid-based sample approach, accounting for sampling variability in the marginal pi.
ICA.BinCont | Assess surrogacy in the causal-inference single-trial setting in the binary-continuous case
ICA.ContCont | Assess surrogacy in the causal-inference single-trial setting (Individual Causal Association, ICA) in the Continuous-continuous case
ICA.ContCont.MultS | Assess surrogacy in the causal-inference single-trial setting (Individual Causal Association, ICA) using a continuous univariate T and multiple continuous S
ICA.ContCont.MultS.MPC | Assess surrogacy in the causal-inference single-trial setting (Individual Causal Association, ICA) using a continuous univariate T and multiple continuous S, by simulating correlation matrices using a modified algorithm based on partial correlations
ICA.ContCont.MultS.PC | Assess surrogacy in the causal-inference single-trial setting (Individual Causal Association, ICA) using a continuous univariate T and multiple continuous S, by simulating correlation matrices using an algorithm based on partial correlations
ICA.ContCont.MultS_alt | Assess surrogacy in the causal-inference single-trial setting (Individual Causal Association, ICA) using a continuous univariate T and multiple continuous S, alternative approach
ICA.Sample.ContCont | Assess surrogacy in the causal-inference single-trial setting (Individual Causal Association, ICA) in the Continuous-continuous case using the grid-based sample approach
ISTE.ContCont | Individual-level surrogate threshold effect for continuous normally distributed surrogate and true endpoints.

## -- L --

LongToWide | Reshapes a dataset from the 'long' format (i.e., multiple lines per patient) into the 'wide' format (i.e., one line per patient)

## -- M --

MarginalProbs | Computes marginal probabilities for a dataset where the surrogate and true endpoints are binary
MaxEntContCont | Use the maximum-entropy approach to compute ICA in the continuous-continuous sinlge-trial setting
MaxEntICABinBin | Use the maximum-entropy approach to compute ICA in the binary-binary setting
MaxEntSPFBinBin | Use the maximum-entropy approach to compute SPF (surrogate predictive function) in the binary-binary setting
MICA.ContCont | Assess surrogacy in the causal-inference multiple-trial setting (Meta-analytic Individual Causal Association; MICA) in the continuous-continuous case
MICA.Sample.ContCont | Assess surrogacy in the causal-inference multiple-trial setting (Meta-analytic Individual Causal Association; MICA) in the continuous-continuous case using the grid-based sample approach
MinSurrContCont | Examine the plausibility of finding a good surrogate endpoint in the Continuous-continuous case
MixedContContIT | Fits (univariate) mixed-effect models to assess surrogacy in the continuous-continuous case based on the Information-Theoretic framework

## -- O --

Ovarian | The Ovarian dataset

## -- P --

plot Causal-Inference BinBin | Plots the (Meta-Analytic) Individual Causal Association and related metrics when S and T are binary outcomes
plot Causal-Inference BinCont | Plots the (Meta-Analytic) Individual Causal Association and related metrics when S is continuous and T is binary
plot Causal-Inference ContCont | Plots the (Meta-Analytic) Individual Causal Association when S and T are continuous outcomes
plot FixedDiscrDiscrIT | Provides plots of trial-level surrogacy in the Information-Theoretic framework
plot Information-Theoretic | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework
plot Information-Theoretic BinCombn | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework when both S and T are binary, or when S is binary and T is continuous (or vice versa)
plot ISTE.ContCont | Plots the individual-level surrogate threshold effect (STE) values and related metrics
plot MaxEnt ContCont | Plots the sensitivity-based and maximum entropy based Individual Causal Association when S and T are continuous outcomes in the single-trial setting
plot MaxEntICA BinBin | Plots the sensitivity-based and maximum entropy based Individual Causal Association when S and T are binary outcomes
plot MaxEntSPF BinBin | Plots the sensitivity-based and maximum entropy based surrogate predictive function (SPF) when S and T are binary outcomes.
plot Meta-Analytic | Provides plots of trial- and individual-level surrogacy in the meta-analytic framework
plot MinSurrContCont | Graphically illustrates the theoretical plausibility of finding a good surrogate endpoint in the continuous-continuous case
plot PredTrialTContCont | Plots the expected treatment effect on the true endpoint in a new trial (when both S and T are normally distributed continuous endpoints)
plot SPF BinBin | Plots the surrogate predictive function (SPF) in the binary-binary settinf.
plot SPF BinCont | Plots the surrogate predictive function (SPF) in the binary-continuous setting.
plot.BifixedContCont | Provides plots of trial- and individual-level surrogacy in the meta-analytic framework
plot.BimixedContCont | Provides plots of trial- and individual-level surrogacy in the meta-analytic framework
plot.comb27.BinBin | Plots the distribution of prediction error functions in decreasing order of appearance.
plot.Fano.BinBin | Plots the distribution of R^2_{HL} either as a density or as function of pi_{10} in the setting where both S and T are binary endpoints
plot.FixedBinBinIT | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework when both S and T are binary, or when S is binary and T is continuous (or vice versa)
plot.FixedBinContIT | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework when both S and T are binary, or when S is binary and T is continuous (or vice versa)
plot.FixedContBinIT | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework when both S and T are binary, or when S is binary and T is continuous (or vice versa)
plot.FixedContContIT | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework
plot.FixedDiscrDiscrIT | Provides plots of trial-level surrogacy in the Information-Theoretic framework
plot.ICA.BinBin | Plots the (Meta-Analytic) Individual Causal Association and related metrics when S and T are binary outcomes
plot.ICA.BinCont | Plots the (Meta-Analytic) Individual Causal Association and related metrics when S is continuous and T is binary
plot.ICA.ContCont | Plots the (Meta-Analytic) Individual Causal Association when S and T are continuous outcomes
plot.ICA.ContCont.MultS | Plots the Individual Causal Association in the setting where there are multiple continuous S and a continuous T
plot.ICA.ContCont.MultS_alt | Plots the Individual Causal Association in the setting where there are multiple continuous S and a continuous T
plot.ISTE.ContCont | Plots the individual-level surrogate threshold effect (STE) values and related metrics
plot.MaxEntContCont | Plots the sensitivity-based and maximum entropy based Individual Causal Association when S and T are continuous outcomes in the single-trial setting
plot.MaxEntICA.BinBin | Plots the sensitivity-based and maximum entropy based Individual Causal Association when S and T are binary outcomes
plot.MaxEntSPF.BinBin | Plots the sensitivity-based and maximum entropy based surrogate predictive function (SPF) when S and T are binary outcomes.
plot.MICA.ContCont | Plots the (Meta-Analytic) Individual Causal Association when S and T are continuous outcomes
plot.MinSurrContCont | Graphically illustrates the theoretical plausibility of finding a good surrogate endpoint in the continuous-continuous case
plot.MixedContContIT | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework
plot.PPE.BinBin | Plots the distribution of either PPE, RPE or R^2_{H} either as a density or as a histogram in the setting where both S and T are binary endpoints
plot.PredTrialTContCont | Plots the expected treatment effect on the true endpoint in a new trial (when both S and T are normally distributed continuous endpoints)
plot.Single.Trial.RE.AA | Conducts a surrogacy analysis based on the single-trial meta-analytic framework
plot.SPF.BinBin | Plots the surrogate predictive function (SPF) in the binary-binary settinf.
plot.SPF.BinCont | Plots the surrogate predictive function (SPF) in the binary-continuous setting.
plot.SurvSurv | Provides plots of trial- and individual-level surrogacy in the Information-Theoretic framework when both S and T are time-to-event endpoints
plot.TrialLevelIT | Provides a plots of trial-level surrogacy in the information-theoretic framework based on the output of the 'TrialLevelIT()' function
plot.TrialLevelMA | Provides a plots of trial-level surrogacy in the meta-analytic framework based on the output of the 'TrialLevelMA()' function
plot.TwoStageSurvSurv | Plots trial-level surrogacy in the meta-analytic framework when two survival endpoints are considered.
plot.UnifixedContCont | Provides plots of trial- and individual-level surrogacy in the meta-analytic framework
plot.UnimixedContCont | Provides plots of trial- and individual-level surrogacy in the meta-analytic framework
Pos.Def.Matrices | Generate 4 by 4 correlation matrices and flag the positive definite ones
PPE.BinBin | Evaluate a surrogate predictive value based on the minimum probability of a prediction error in the setting where both S and T are binary endpoints
Pred.TrialT.ContCont | Compute the expected treatment effect on the true endpoint in a new trial (when both S and T are normally distributed continuous endpoints)
Prentice | Evaluates surrogacy based on the Prentice criteria for continuous endpoints (single-trial setting)
PROC.BinBin | Evaluate the individual causal association (ICA) and reduction in probability of a prediction error (RPE) in the setting where both S and T are binary endpoints

## -- R --

RandVec | Generate random vectors with a fixed sum
Restrictions.BinBin | Examine restrictions in pi_{f} under different montonicity assumptions for binary S and T

## -- S --

Schizo | Data of five clinical trials in schizophrenia
Schizo_Bin | Data of a clinical trial in Schizophrenia (with binary outcomes).
Schizo_BinCont | Data of a clinical trial in schizophrenia, with binary and continuous endpoints
Schizo_PANSS | Longitudinal PANSS data of five clinical trials in schizophrenia
Sim.Data.Counterfactuals | Simulate a dataset that contains counterfactuals
Sim.Data.CounterfactualsBinBin | Simulate a dataset that contains counterfactuals for binary endpoints
Sim.Data.MTS | Simulates a dataset that can be used to assess surrogacy in the multiple-trial setting
Sim.Data.STS | Simulates a dataset that can be used to assess surrogacy in the single-trial setting
Sim.Data.STSBinBin | Simulates a dataset that can be used to assess surrogacy in the single trial setting when S and T are binary endpoints
Single.Trial.RE.AA | Conducts a surrogacy analysis based on the single-trial meta-analytic framework
SPF.BinBin | Evaluate the surrogate predictive function (SPF) in the binary-binary setting (sensitivity-analysis based approach)
SPF.BinCont | Evaluate the surrogate predictive function (SPF) in the binary-continuous setting (sensitivity-analysis based approach)
SurvSurv | Assess surrogacy for two survival endpoints based on information theory and a two-stage approach

## -- T --

Test.Mono | Test whether the data are compatible with monotonicity for S and/or T (binary endpoints)
TrialLevelIT | Estimates trial-level surrogacy in the information-theoretic framework
TrialLevelMA | Estimates trial-level surrogacy in the meta-analytic framework
TwoStageSurvSurv | Assess trial-level surrogacy for two survival endpoints using a two-stage approach

## -- U --

UnifixedContCont | Fits univariate fixed-effect models to assess surrogacy in the meta-analytic multiple-trial setting (continuous-continuous case)
UnimixedContCont | Fits univariate mixed-effect models to assess surrogacy in the meta-analytic multiple-trial setting (continuous-continuous case)