JMP Clinical. Getting Started with. JMP Clinical. Version 3.1

Transcription

1 JMP Clinical Version 3.1 Getting Started with JMP Clinical Creativity involves breaking out of established patterns in order to look at things in a different way. Edward de Bono JMP, A Business Unit of SAS SAS Campus Drive Cary, NC 27513

2 Getting Started with JMP Clinical Copyright 2011, SAS Institute Inc., Cary, NC, USA All rights reserved. Produced in the United States of America. Your use of this publication shall be governed by the terms established by the vendor at the time you acquire this publication. U.S. Government Restricted Rights Notice: Use, duplication, or disclosure of this software and related documentation by the U.S. government is subject to the Agreement with SAS Institute and the restrictions set forth in FAR , Commercial Computer Software-Restricted Rights (June 1987). SAS Institute Inc., SAS Campus Drive, Cary, North Carolina JMP, SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc. in the USA and other countries. indicates USA registration. Other brand and product names are registered trademarks or trademarks of their respective companies.

3 Getting Started with JMP Clinical Checking the Software Installation 1 To verify that the software is installed properly, from the Clinical Starter window, select Demographics > Distribution, as shown below. 1. Note: This document assumes that JMP Clinical 3.1 has been successfully installed on your desktop machine. If you still need to install JMP Clinical 3.1 on your machine, consult the Installation Instructions for JMP Clinical 3.1 guide (

4 2 Getting Started with JMP Clinical 3.1 If a JMP Alert error message is generated stating that the file cannot be found, select General Utilities > Generate Clinical Dialogs from XML from the Clinical Starter window. 2 From the resulting Application Process (AP) window, select Load from the buttons at the bottom of the window, as shown below. 3 From the Load Setting window, select Example Setting (circled, below) 4 Select Nicardipine from the Select a Setting list and click OK (circled, below).

5 Getting Started with JMP Clinical Click Run (circled below). Getting Started with JMP Clinical 3.1 The process should run in a few seconds and generate graphical outputs, which will be described later.

6 4 Getting Started with JMP Clinical 3.1 Study Registration and Variable Checking To analyze a new study in JMP Clinical, you must first register it. Data for a study must be in either SDTM format (e.g. with SAS data sets dm.sas7bdat, ae.sas7bdat, and so on) or ADaM format (e.g. adsl.sas7bdat), and a subset of SDTM variables are required in each data set. JMP Clinical provides a way to check the variables in a registered study to verify it can be analyzed in the software. Below we will be working with the supplied Nicardipine data set for example purposes. It has already been registered during installation, but we will register it again for illustration purposes. The Add Study from Folders utility registers a study saved on your local machine and defines the folders where the SDTM and/or ADaM files are located along with a default output folder. These values can be changed later if desired with the Manage Study AP, found in the Studies menu of JMP Clinical. 1 From the Clinical Starter window, select Studies > Add Study from Folders. 2 Complete the dialog as shown below: Specify a name for your study Specify the name and path to the folder containing either the SDTM or the ADaM data sets. You can either use the Choose button to browse to the folder or type the name and path in the text field. Note: JMP Clinical accepts data in either SDTM or ADaM format. You must specify either an SDTM or ADaM folder. If SDTM is specified, all of the SDTM data sets must be in the same folder. Likewise, if ADaM is specified, all of the ADaM data sets must be in the same folder. You can specify both SDTM and ADaM. The preferred specification is SDTM plus the corresponding adsl.sas7bdat ADaM data set.

7 Getting Started with JMP Clinical You can specify a folder containing optional supplementary data or MedDRA terms. You can either use the Choose button to browse to the folder or type the name and path in the text field. Check the Import SAS Transport Files check box if your data is contained in SAS transport files. Specify a folder in which to place the study metadata file(s). To avoid any potential confusion or conflicts as you work through this example, we recommend that the output folder that you select is new and empty. 3 Click Run (circled in the figure above) to start the process. The following JMP Clinical Message window is surfaced when the process is complete. Once the study has been added, the next step is to check the data sets to determine whether the variables that JMP Clinical requires are available. This is a check for SDTM or ADaM compliance, but only for the subset of variables required by JMP Clinical. This process determines whether the variables required for the software to function are in the appropriate domains, and is designed to be as streamlined and forgiving as possible. You can perform this process from either the JMP Clinical Message window shown above or from the Clinical Starter window. 4 Click Check Required Variables in the JMP Clinical Message window shown above (or select Studies > Check Required Variables from the Clinical Starter window). 5 Select the study from the Study pull-down menu. In this case, we will be using the Nicardipine data, so you can choose either Nicardipine or Nicardipine_1. Getting Started with JMP Clinical 3.1

8 6 Getting Started with JMP Clinical Click the Open button next to the Required Variables Data Set text box to open the data set that is used to compare your variables to a list of expected variables. Note: JMP Clinical processes require 109 variables. Some of these variables are redundant (i.e the software can use different variables for the same purpose, depending on the study's design). The Options tab has fields to name the output file and the.jsl file that creates the graphic interface. Default names are created if these are left blank. When defaults are used, the results will be overwritten with each new analysis from the same study unless the output directory is changed 7 Click Run. A.pdf report with several tables listing results of the check, is generated. The most useful tables are those that listing miss variables and affected processes.

9 Getting Started with JMP Clinical Getting Started with JMP Clinical 3.1 In this example, the SAS Variable, VISITNUM is not available from the ex (exposure) domain. Because this variable is missing, we cannot select the Cycles option from some of the downstream application processes. Note: JMP Clinical looks for the domain name (e.g., DM, AE, CM) and the SAS Variable name when checking for required variables. The SAS Label is not used. Basic Safety Workflow To get an initial overview of the data, the Basic Safety Workflow is the best starting point. This runs a number of different processes and provides a comprehensive initial assessment of the data. In this example, we will use the Nicardipine data for understanding how to interpret the graphs and the various tools to drill down into the data. As some of the outputs are structured similarly (e.g., the Interventions Incidence Screen and AE Incidence Screen), we will not cover each result in depth. Rather, we will review each type of output. 1 Select Workflows > Basic Safety Workflow from the Clinical Starter.

10 8 Getting Started with JMP Clinical 3.1 In this example, we use the Nicardipine study. The Actual treatment arm will be used as the variable for any comparison analyses. The Planned arm or a selected variable can be used instead if desired. Note: A feature of JMP Clinical is that when a selection is made in one process and the process run, that selection or setting carries through the analysis until it is actively changed. 2 Click on the Populations tab. The Populations tab allows for the selection of different populations of individuals to be analyzed. This tab is present on a number of APs. 3 Click on the Options tab.

11 Getting Started with JMP Clinical Getting Started with JMP Clinical 3.1 The Options tab lists the processes to be run in the workflow and also allows for the selection of Term Levels to be used in the AE Incidence Screen. In this example, we will use the defaults for the Nicardipine data set. 4 Click Run. A number of processes run in sequence. When the run is complete a JMP journal containing the results will be surfaced, as shown below.

12 10 Getting Started with JMP Clinical 3.1 The Workflow Builder dialog, displaying all the processes just run, or the Basic Safety Workflow dialog can be opened by clicking either of the buttons at the top. The buttons to launch the results from each process are under the outline headers of Demographics Results, Interventions, Events, and Findings. We will examine each of these sections, as follows: Demographics Results 1 Expand the Demographics Distribution results by clicking on the triangle next to the outline header. 2 Click on the DMDistribution link to launch the results. The DMDistribution dashboard is shown below.

13 Getting Started with JMP Clinical The dashboard contains several features that are described below. These features are found in the dashboards of most analytical processes. Tabs Panes. Many APs produce more graphics than can be conveniently displayed. To facilitate analysis, results are grouped thematically into one or more tabs. The results of the analysis shown here include one tab. From left to right at the top of the dashboard, distributions of Age, Sex, Treatment Arm, and Study Site Identifier are displayed. Note that in this instance, Planned Treatment is used instead of the selected Actual Treatment. The Actual Treatment was not present in the domain used (adsl) and so the Planned was substituted. On the next line is a One-way analysis of Age by Treatment Arm, a Mosaic Plot of Sex by Treatment Arm and a Mosaic Plot of Race by Treatment Arm. The contingency tables or values associated with each plot are below the graph. In some cases, the values are not visible. Click on the arrows to view the tables. A Data Filter, which can be used to dynamically subdivide the data for closer analyses, is located to the right of the graphics The Tabs Selector. An interactive list of all of the tabs is located at the upper left of the dashboard. Each tab consists of a drop-down menu that can be used to view the tab in the Tabs Pane or in a new window, to view the data set containing the data used to generate the graphics, and to view the SAS log. Getting Started with JMP Clinical 3.1

14 12 Getting Started with JMP Clinical 3.1 The Action Buttons are platform result-specific drill down capabilities. When selections of subsets of the data are made, further analyses (e.g. subject profiles, subject clustering) can be performed on those selections. 3 Scroll right to the Data Filter. Check the Show and Include check boxes. Clicking on the different options in the Data Filter will filter the graphics and the values. For example, clicking on F under Sex will present values for only the Females in the data set. You can select additional AND filters by holding the Ctrl key. For example, after selecting F under Sex, the calculated values can be further restricted to WHITE under Race by selecting that value from the list. The continuous variable Age can be adjusted with the slider or by clicking into the numeric field (e.g., 18) and typing a new value. 4 Additional values can be added to the filter by clicking the + (AND) or the (OR), and then selecting variables from the resulting list. For example, if you want to be able to filter by site, click the +, then select Study Site Identifier from the list and then click Add as shown below.

15 Getting Started with JMP Clinical Getting Started with JMP Clinical Click the Clear button at the top of the Data Filter to clear out any filtered values. 6 Click on the NIC.15 histogram in the Planned Treatment for Period 01 panel, as shown below. JMP graphics are dynamically linked: when you select rows by clicking on one figure, the corresponding rows are highlighted in all of the other graphics (and data tables). 7 Click on the Close this Window and Associated Graphics button located to the left of the dashboard below the Action Buttons.

16 14 Getting Started with JMP Clinical 3.1 Interventions - Exposure 1 Expand the Interventions outline on the Workflow Journal and then open the Exposure Results outline. 2 Click Exposure Summary to view the results. An exposure summary rtf file is generated, which contains the study summarized values as well as the duration of study treatment and number of subjects, summarized by the default selection Duration Time Window of 7. 3 Examine the Exposure Summary dashboard.

17 Getting Started with JMP Clinical Getting Started with JMP Clinical 3.1 The Exposure Summary tab shows the number of subjects by study days, separated by treatment arms. This enables you to see whether there is a bias in the different groups in the study. 4 Click on the Duration Distribution tab. This tab is similar to the Demographics Distribution output results.

18 16 Getting Started with JMP Clinical Under the Data Filter, highlight one of the SITEIDs that has a reasonable number of samples, then from the Action Buttons on the left side of the dashboard, select Cluster Subjects. This will create a cross domain cluster of subjects, so you can see whether there are any similarities among the selected subjects across domains. Subjects are on the x-axis and the domain identifiers are on the y-axis. 6 Highlight a group of subjects in the CM Indications tab by clicking on a section of the dendrogram on the right

19 Getting Started with JMP Clinical Getting Started with JMP Clinical Click along the remaining tabs across the top of the dashboard. Note that the selected subjects are highlighted in figures on all tabs. When numeric values are used (LB, VS and EG Measurements), additional graphs are shown along with the clustered values among the subjects. 8 Click on the Close this Window and Associated Graphics and Results Tables button on each open dashboard to close. Interventions - Concomitant Medication Results 1 From the Workflow Journal, expand the Concomitant Medication Results outline. There are two results generated from the workflow: InterventionsDistribution and InterventionsIncidenceScreen. 2 Open and examine the output for InterventionsDistribution. The graphics and filter function similarly to that of the DM Distributions. We will review Incidence Screen results under Adverse Events (below). Adverse Events Mortality Kaplan-Meier 1 From the Workflow Journal, expand the Events outline, then the Mortality Results outline.

20 18 Getting Started with JMP Clinical Click on MortalityKaplanMeier to launch the results. The dashboard has one tab containing two plots. The Kaplan-Meier curves and the associated statistics are toward the left-hand side of the dashboard. In this case, it is clear that there is no significant difference in mortality between the two treatments. The mosaic plot and associated contingency table are located on the right-hand side of the dashboard. This plot graphically demonstrates that the proportion of subject death during the study does not differ between the treatment arms. 3 Click on Close this Window and Associated Graphics and Results Tables to close this dashboard. Adverse Events _ AE Distribution 1 From the Workflow Journal, expand the Adverse Events outline.

21 Getting Started with JMP Clinical Click on the AEDistribution link to view the results. This AEDistribution dashboard is similar to the one shown in Demographics Results with one exception - there is now a Tree Map of the Dictionary-Derived Term, as shown below. Getting Started with JMP Clinical 3.1 The Dictionary-Derived terms are sized according to how many reports were generated in the study. Remember that a subject can experience an adverse event more than once. You can see that Vasoconstriction (circled above) has a high number of reports for this adverse event in the study. Hovering over the Vasoconstriction field will bring up the number of reports, 693. These results can be filtered using the Data Filter to the right of the dashboard as demonstrated previously. We will show how the Graph Builder can be used to create other views. 3 Select Clinical > General Utilities > Graph Builder from the menu bar at the top of the dashboard to open the Graph Builder utility. 4 Select Study Site Identifier from the panel on the left and drag it to the x-axis as shown below.

22 20 Getting Started with JMP Clinical Go back to the AEDistribution dashboard, and click on the "+" at the bottom of the filter to add Dictionary-Derived Term to the filtering terms. 6 Click the Red Triangle next to the Dictionary-Derived Term filter, and from the menu, select Order By Count. 7 Check the Show and Include boxes at the top of the Data Filter.

23 Getting Started with JMP Clinical Compare the histogram above with the non-filtered histogram. Note how they vary across the different sites. 9 Click on Close this Window and Associated Graphics and Results Tables to close this dashboard. Getting Started with JMP Clinical 3.1 Adverse Events - AE Incidence Screen 1 From the Workflow Journal, click on the AEIncidenceScreen (Preferred Term) link to view the results.

24 22 Getting Started with JMP Clinical 3.1 This Relative Risk volcano plot is a graphical representation of the significant relative risks by preferred term. The x-axis is the log 2 value of the relative risk. Positive values are associated with Nicardipine treatment and negative values are associated with placebo. The y-axis is the -log 10 (Raw p-value) for each relative risk. The dotted red line represents the False Discovery Rate (FDR) corrected p-value cutoff, which in this case is Thus, any value above this line and to the right of 0 has a relative risk that is significantly greater in the Nicardipine group, and points above the line to the left of 0 have a significantly elevated risk in the placebo group. Phlebitis, hypotension, and isosthenuria are elevated in the treatment group. We can drill down on this with the Action Buttons to the left of the dashboard. 2 Highlight the Phlebitis, Hypotension, and Isosthenuria bubbles in the plot by drawing a rectangle around them with your mouse.

25 Getting Started with JMP Clinical Getting Started with JMP Clinical Click Venn Diagram in the Action Buttons pane.

26 24 Getting Started with JMP Clinical There are 25 individuals that had both hypotension and phlebitis. Highlight that number by clicking on it, and then click Profile Subjects as shown above. 5 When the Profile is generated, select Normal (circled below) in the Display Mode for Findings panel on the left side of the patient profiler dashboard. 6 Examine the Patient Profile.

27 Getting Started with JMP Clinical Each Subject's profile is shown individually. You can remove views from within the profile graphic by expanding the outlines to the left and unchecking the boxes within each domain category. The legends are located to the right of the profile, and comments can be added for each individual. Selecting each subject separately will in turn create the profile for each respective subject. Multiple subjects can be shown in a single profile by selecting them from the Subjects box. 7 Select the first subject from the Subjects box, then while holding the Shift key down, select the fifth subject. You should have the top five subjects highlighted. Getting Started with JMP Clinical 3.1 The Profiler automatically updates to show data for the five selected patients.

28 26 Getting Started with JMP Clinical 3.1 In the partial view above, multiple lines for a single Adverse Events value indicate that multiple subjects experienced it. For example, two subjects experienced Anemia (circled) during the study period. 8 Click Create Narratives in the lower left side of the Profile Subjects dashboard.

29 Getting Started with JMP Clinical Getting Started with JMP Clinical Select the Options tab from the resulting AE Narrative application process window and select any desired options.

30 28 Getting Started with JMP Clinical Click Run. A Patient Narrative (partially shown below) is created in MS Word for each patient selected in the Profile Subjects dashboard. This narrative can be edited as desired.

31 Getting Started with JMP Clinical Getting Started with JMP Clinical Close the Profiler and the Venn Diagram windows and return to the AE Incidence Screen dashboard. The Dot Plot and Relative Risk Plot action buttons will create more traditional views of values highlighted in the Volcano Plot. 12 Highlight a number of points in the Volcano Plot as before, and then click Tabulate from the Action Buttons pane to create a table with a 0-1 indicator for each subject.

32 30 Getting Started with JMP Clinical Drag the Unique Subject Identifier to the table as shown below The modified table is partially shown below:

33 Getting Started with JMP Clinical Click the red triangle at the top (circled next to Tabulate) and select Make into Data Table. Getting Started with JMP Clinical 3.1 The values in the resulting table can be further analyzed with numerous JMP Clinical analytic tools (e.g., hierarchical clustering, Venn diagrams). 15 Close all open tables and figures except for the Workflow Journal.

34 32 Getting Started with JMP Clinical 3.1 Adverse Events - Treatment Emergent AE Summary 1 From the Workflow Journal, click on the TreatmentEmergentAESummary link to view the results. A histogram from the Graph Builder is generated on the results dashboard. These can be explored and filtered with the embedded Data Filter. A separate rtf file with the Treatment Emergent AE Summary is generated with the data in tabular form. 2 Close all open tables and figures except for the Workflow Journal. Disposition Results - Events Distribution 1 Expand the Disposition Results outline by clicking on the triangle next to the header. 2 Click on the EventsDistribution (Disposition) link to launch the results. These results are similar to those of the previously viewed distributions. 3 Close all open tables and figures except for the Workflow Journal. Findings - Labs Baseline ANOVA 1 Expand the Findings outline. 2 Expand the Labs Results outline. 3 Click on the FindingsBaselineANOVA link to view the results.

35 Getting Started with JMP Clinical These results are also presented in a summary volcano plot. In this case, the difference between the Nicardipine and placebo is on the x-axis, and the -log 10 (p-value) for that difference is on the y-axis. The dotted red line represents the FDR corrected-log 10 (p-value) for significance. Clearly WBC and BUN are significantly elevated in the Nicardipine versus the placebo group. The dendrogram to the right shows the clustering of the LSmean values for the significant findings between the two treatment arms. Similarly changed values will tend to be in the same cluster. Further to the right is a Parallel Plot with the LSmean values of the significant findings as well as these findings in 2-dimensional principal component space. 4 Highlight the WBC and BUN points in the volcano plot. From the Action Buttons on the left, click on the Box Plots button Getting Started with JMP Clinical 3.1 For each selection, box plots by study day (default = 7 groups) are generated. Each point represents a subject, and the Profile Subjects, Cluster Subjects, or Apply Subject Filter function under the Action Buttons can be applied after selecting points on the plot 5 Close the Box Plots window.

36 34 Getting Started with JMP Clinical From the ANOVA Results window and with WBC and BUN still selected, click Shift Plots (under Action Buttons). A shift plot is created for each point selected from the ANOVA result's volcano plot. The x-axis is the baseline value/upper limit normal, and the y-axis is the overall trial mean/upper limit normal. Changes in a subject over the course of the trial are seen as points deviating from the solid line, either positively or negatively. 7 Close the Shift Plots window. 8 From the ANOVA Results window and with WBC and BUN still selected, click Construct Oneway Plots (under Action Buttons).

37 Getting Started with JMP Clinical Getting Started with JMP Clinical 3.1 Two plots are generated from each point selected in the volcano plot. The top plot in each pair is the one-way analysis with box plots and mean/standard deviation indicators. To compare the mean values, click on the Red Triangle next to the Oneway Analysis and choose the desired Compare Means function from the pull-down menu. The lower plot in each pair is a density plot. Here we can see that there is a trend for WBC values to be larger in the Nicardipine group versus the placebo group (i.e., the Nicardipine curve is right shifted compared with the placebo curve).

38 36 Getting Started with JMP Clinical Close all open tables and figures except for the Workflow Journal. Findings - Labs Bubble Plot 1 Click on the FindingsBubblePlot link to view the results. The bubble plot is a graph that enables you to see values changing over a time period. In this instance, we are looking at Alanine Amino Transferase versus Bilirubin. Each point represents a patient, and the time is the day of study, starting at -3. Clicking on the Go button at the bottom will start the time sequence. The key for the log 2 values of ULN represented on the axes are to the right of the figure. The x- and y-axes values can be changed by clicking on the X or Y directly above the graph. This will bring up a Select Columns dialog. Drill-downs with the Action Buttons on the left can be used for highlighted values in the plot. 2 Click Go and let the figure run to approximately day 10, and then click Stop and highlight the two samples as shown below.

39 Getting Started with JMP Clinical Click Graph Time Trends from the Action Buttons pane. Getting Started with JMP Clinical 3.1 The time trend plot is created in the Graph Builder window for these two subjects.

40 38 Getting Started with JMP Clinical 3.1 Note that the values are linearly interpolated between measurements. 4 Highlight BUN (Blood Urea Nitrogen) and CREAT (Creatinine) from the Select Columns chooser to the left of the plot, and then drag and drop them onto the y-axis as shown below. This process lets you overlay more values onto the initial graph. In this case, we can track the values for renal function overlaid with those indicators for hepatic failure 5 Close all open tables and figures except for the Workflow Journal. Findings - Hy s Law Screening 1 Click on the HysLawScreening link to view the results.

41 Getting Started with JMP Clinical Getting Started with JMP Clinical 3.1 In this portion of the output, each point represents a subject and on the lower row of graphs for example, the BILI/ULN on the y-axis is plotted versus (from left to right), ALT/ULN, AST/ULN, and ALP/ ULN, respectively. Subjects can be highlighted and the drill downs under the Action Buttons pane can be used as shown before. 2 Click on the 3D Scatterplot tab to view a three-dimensional representation of the scatterplot matrix with ALT/ULN, AST/ULN and BILI/ULN as the default axes.

42 40 Getting Started with JMP Clinical 3.1 This completes the review of the workflow results. Before continuing onto the next section, close the Workflow Journal. The results can be brought up again by opening the journal file (.jrn) from the output directory for this JMP Clinical study. Dynamic Visualization of Time Courses We have already seen how the bubble plot in JMP allows for the visualization of lab findings changing over time. You can also create outputs from other applications in JMP Clinical to see how values change over pre-defined time windows. In this instance, we will use the AE Incidence Screen application. 1 From the Clinical Starter, select Events > AE Incidence Screen. 2 Load the saved settings by clicking on the Load button at the bottom of the application process window, clicking on the Example Settings button in the Load Setting window, and then choosing Nicardipine. 3 Click on the Options tab. 4 In the Trial Time Windows field on the Options tab, enter the following values: [1,3] [3,6] [6,9] [9,12]. The Options tab should look like the figure below.

43 Getting Started with JMP Clinical Getting Started with JMP Clinical Click Run. A bubble plot and data filter are generated.

44 42 Getting Started with JMP Clinical Click on the Dictionary-Derived Term Exploding Volcano tab. A plot of the filtered data is shown.

45 Getting Started with JMP Clinical Getting Started with JMP Clinical Click Go or Step below the bubble plot.

46 44 Getting Started with JMP Clinical 3.1 In this case, we can see that over the time windows, Phlebitis increases in relative risk and -log 10 (p-value) whereas Hypotension decreases. The size of the points represents the number of reports of each adverse event. Conclusion This concludes the getting started session with JMP Clinical 3.1. There are more functions available from the Clinical Starter window, and there are advanced functions such as model selection, partial correlations and predictive modeling. The specific JMP Clinical applications all function similarly to the ones that we have reviewed here. Details can be found in the online manual by selecting Documentation and Help > User Guide from the Clinical Starter window or by clicking the User Guide button at the bottom of any process dialog.