Co-occurrence

The Co-occurrence report enables users to explore pairs of occurrences, including adverse events (AE), concomitant medications (CM), and deaths, that occur within the same patient and overlap in time. The report estimates the durationof overlap in days for each occurrence pair. Users can compare the overlap of occurrences to the marginal frequencies where occurrences happen individually. Occurrence pairs will be presented by treatment to assess if certain pairs occur more frequently than others within specific treatments or to compare the amount of time pairs occur together within treatment. This report evaluates occurrences from multiple sources, including adverse events from the AE domain, concomitant medications from the CM domain, or deaths identified by the presence of a death date in either DM or ADSL.

Unlike the Nearby Occurrences report that requires users to identify one or more reference occurrences of interest and then examine other occurrences that fall within a user-defined time window, Co-occurrence evaluates all possible pairs of occurrences that match the Term of Interest and identifies those that overlap in time within a patient. The Nearby Occurrences report is best suited for investigating specific terms of interest, whereas the Co-occurrence report examines overlap for all terms to see what relationships might arise.

Methodology

Pairs are built from potentially multiple instances of the individual components present in the data. In other words, when records are joined, two or more potentially overlapping periods involving the same Terms of Interest (for example, phenobarbital and dexamethasone) might be identified within a study. However, the current implementation does not attempt to identify or distinguish separate overlap periods between the same pair of Terms of Interest. The Number of Days of Overlap is the frequency of unique study days where both Terms of Interest in an Occurrence Group (currently limited to pairs) are observed together.

No attempt is made to assess overlap at the time-of-day level. If two Terms of Interest occur on the same study day, they are considered to overlap with each other.

In practice, missing dates for deaths and AEs are unlikely to occur. However, medications used to treat chronic disease might have unknown starts dates (indicating that the medication was initiated in the distant past) or unknown end dates (implying that the medication is ongoing). Although JMP Clinical makes every effort to impute partial dates according to predefined rules, completely missing dates might still occur in some cases. When start or end dates are missing entirely, they will be imputed using the earliest or latest possible date based on the following rules, evaluated in the order shown according to variable availability:

• Start date: Enrollment date (ENRLDT), informed consent date (RFICDT), or earliest visit start date (JMPC_ASTDT)
• End date: End of study date (EOSDT), end of participation date (RFPENDT), latest visit end date (JMPC_AENDT), or disposition event dates (JMPC_ASTDT).

For instances where stop dates for medications or AEs were not collected as part of the eCRF design, the stop dates are assumed to be the same as the start dates. In other words, the occurrences start and end on the same study day. This assumption is always applied to deaths.

For all studies, occurrences are classified according to the treatment arm, including all treatments for crossover or multi-treatment studies. A potential enhancement of the Co-occurrence report would be to assess the overlap of pairs of Terms of Interest in the context of the treatment being received on a given study day, including periods during which no treatment is administered.

Usage and Interpretation

The primary output is an UpSet Plot, which contains several key components for interpreting the results. UpSet plots are used to communicate the frequencies of subgroups defined by one or more factors and to compare these marginal frequencies with the marginal frequencies of each factor considered individually.

Example 1: Default Settings

The Co-occurrence report was run for Nicardipine using the default settings to demonstrate usage and the interpretation of the results. Figure 1 shows the Upset plot.

Figure 1: UpSet Plot

Features of the UpSet plot are listed below:

• The vertical and horizontal axes are ordered according to frequency, such that the farther right (or down) a values appears in the plot, the smaller its frequency.
• The line-and-dot matrix area of the figure illustrates the connections between Terms of Interest displayed on the Occurrence vertical axis and the Occurrence Groups displayed on the horizontal axis.
• The Bar Chart present on the Overall Frequency of Patients in Occurrence Group vertical axis and the Occurrence Group horizontal axis presents the frequency of each Occurrence Group, which is currently limited to pairs of occurrences. This bar chart is displayed in decreasing order of frequency from left to right.
• The bar chart present in the Occurrence vertical axis and the Overall Frequency of Patients with Occurrences horizontal axis presents the frequency of each Occurrence individually. This bar chart is presented in presented in decreasing order of frequency from top to bottom.
• The top area of the figure, within the Proportion of Treatment vertical axis and the Occurrence horizontal axis, is a stacked bar chart that shows the proportion of Occurrence Group pairs that are attributable to a particular treatment. This part of the graph has numerous additional options that are discussed further below.

For example, phenobarbital and dexamethasone are the left-most pair of terms, indicating that they occur with the greatest frequency (n = 470) among all possible pairs of terms. This overlap in Terms of Interest can be compared with the individual marginal frequencies of phenobarbital (n = 695) and dexamethasone (n = 599). In other words, 695-470=225 patients had phenobarbital with no overlapping dexamethasone, while 599-470=129 patients had dexamethasone with no overlapping phenobarbital. The underlined text highlights a very important distinction about the Co-occurrence report, which specifically looks for pairs of Terms of Interest that overlap in time within a patient. A patient could receive both phenobarbital and dexamethasone, but if the two drugs do not overlap on the same study days, that patient is not counted among the 470 patients with overlapping phenobarbital and dexamethasone.

So, among the 225 patients with phenobarbital and no overlapping dexamethasone:

• A subset will not have received dexamethasone at all.
• The remaining patients will have received some dexamethasone, but not on the same study days as phenobarbital.

Similarly, among the 129 patients with dexamethasone and no overlapping phenobarbital:

• A subset will not have received phenobarbital at all.
• The remaining patients will have received some phenobarbital, but not on the same study days as dexamethasone.

Of the 470 patients with the “Dexamethasone, Phenobarbital” pair, 0.48 and 0.52 of them occur in patients receiving Nicardipine or Placebo, respectively. Marginal counts for each treatment are visible in the data table, or the user can click Frequencies by Treatment to change the bar charts to side-by-side bar charts displaying sample sizes for each treatment (Figure 3). Although filtering might be required to view treatment-specific sample sizes, we can observe that 230 and 240 patients receiving Nicardipine or Placebo, respectively, had the “Dexamethasone, Phenobarbital” pair.

The Number of Days of Overlap table (Figure 2) lists summary statistics for the Number of Days of Overlap by treatment and overall.

Figure 2: Number of Days of Overlap table

Other summary statistics for the Number of Days of Overlap are available in the data table.

Note: Summary statistics with the word “Overall” contained in the column name are across all treatments, while the others are specific to the treatment listed in a given row.

Options

Data - Adverse Events

Term Level

Use this option to specify which level of terms to use as categories.

Possible term levels are report-specific and are listed in the following table:

Term Level

Corresponding Variable

Function

Preferred Term (PT)

AEDECOD in AE
• Uses a dictionary-derived text description of the adverse event, listed in the AEDECOD column in AE, that defines the corresponding value in the AETERM or AEMODIFY column.
• A preferred term is restricted to a single medical concept.

Verbatim Term (VT)

AETERM in AE
• Select this option to use the term as listed in the adverse event term variable.
• Verbatim terms are identified by values within the reported term (AETERM) variable of AE.sas7bdat data set.

Body System

AEBODSYS in AE
• Uses a dictionary-derived text description of the affected body system, listed in the AEBODSYS column in AE.

High(er) Level Term (HLT)

AEHLT in AE
• A superordinate descriptor for multiple preferred terms (PTs).

High(er) Level Group Term (HLGT)

AEHLGT in AE
• A superordinate descriptor for multiple higher level terms (HLTs)

Standard MedDRA Query

 
• Grouping of MedDRA terms, at a defined level, that describes a specific medical condition.

Primary System Organ Class (SOC)

AESOC in AE
• Uses Primary System Organ Class level of adverse events as categories.

Lowest Level Term (LLT)

AELLT in AE
• Uses Lowest Level Term level of adverse events as categories.

Body System or Organ Class

AEBODSYS in AE
• Uses Body System or Organ Class level of adverse events as categories.

Dictionary-Derived Term

AEDECOD in AE
• Uses Dictionary-Derived Term level of adverse events as categories.

Reported Term for the Adverse Event

AETERM in AE
• Uses Reported Term for the Adverse Event level of adverse events as categories.

Reported Name

either CMTRT (for Concomitant Medications) or SUTRT (for Substance Use)
• Uses Reported Name level of intervention as categories.

Standardized Name

either CMDECOD (for Concomitant Medications) or SUDECOD (for Substance Use)
• Uses Standardized Name level of intervention as categories.

Note: Input data determines the availability of options. Not all term levels are available in all of the reports in which term levels are specified.

Note: The dictionary name and version used to generate the descriptions should be included as part of the submission.

Include serious adverse events only

Check this box to include only serious adverse events in the analysis.

Serious events are identified by a “Y” value in the expected AESER variable in the AE or ADAE data sets.

Event Type

Use this feature to specify the inclusion of particular events in the analysis. The selection limits the report to only adverse events of that type.

By default, all events are included in the analysis.

Available options are listed in the following table:

Option:

Select when you want to:

All event types

• Include all events.

Pre treatment events

• Include events that occur before dosing for treated subjects.

Treatment emergent adverse events

• Include events that occur on or after the first dose of study drug.

Note: For information about how treatment emergent-adverse events (TEAEs) are defined, please refer to How does JMP Clinical determine whether an Event Is a Treatment Emergent Adverse Event?.

On treatment events

• Include events that occur on or after the first dose of study drug and at or before the last dose of drug (+ the offset for end of dosing). The date of last dosing is normally taken from EXENDTC. If EXENDTC does not exist, the date is taken from EXSTDTC instead.

Off treatment follow up events

• Include events that occur after the last dose of drug (+ the offset). The date of last dosing is normally taken from EXENDTC. If EXENDTC does not exist, the date is taken from EXSTDTC instead.

Note: When crossover is detected, only those events that occur within the specified treatment period dates are shown. This is true even when All Event Types has been selected. For example, pre-treatment events are not assigned to a treatment and therefore not shown in the report.

Ignore available treatment emergent flags

This option applies only if the selected event type specifies treatment-emergent events. If this option is not checked, then the report will check for existing treatment emergent flags in the data and subset based on those flags. If the option is checked, then the Algorithm JMP Clinical uses to define treatment emergence will be applied.

Data - Concomitant Medications

Term Level

Use this option to specify which level of terms for for interventions to use as categories.

Possible term levels are report-specific and are listed in the following table:

Term Level

Corresponding Variable

Function

Reported Term for the Drug, Med, or Therapy

CMTRT in CM
• Verbatim medication name that is either preprinted or collected on a CRF.

Standardized Medication Name

CMDECOD in CM
• Standardized or dictionary-derived text description of CMTRT. Equivalent to the generic drug name in WHO Drug.
Category for Medication

CMCAT in CM
• Used to define a category of medications/treatments.

Intervention Type

Use this feature to specify the inclusion of particular type of intervention in the analysis. By default, all interventions are included in the analysis.

Available options are listed in the following table:

Option:

Select when you want to:

All intervention types

• Include all interventions.

Pre treatment interventions

• Include interventions that occur before dosing for treated subjects or any event for untreated subjects.

Treatment emergent interventions

• Include interventions that occur on or after the first dose of study drug.

Note: For information about how treatment emergent interventions are defined in JMP Clinical, please refer to How does JMP Clinical determine whether an Event Is a Treatment Emergent Adverse Event?.

On treatment interventions

• Include interventions that occur on or after the first dose of study drug and at or before the last dose of drug.

Off treatment follow up interventions

• Include interventions that occur after the last dose of drug.

Note: When crossover is detected, only those interventions that occur within the specified treatment period dates are shown. This is true even when All Intervention Types has been selected.

Truncate data to the start of the study

Check this option to truncate start dates to use (in order) enrollment date, informed consent date, or earliest visit date. Note: Checking this option does not delete records (generally medications) if they start prior to the study.

Display

Upset Format

UpSet plots are used to communicate the frequency of subgroups produced according to one or more factors compared with the marginal frequencies of considering each factor alone.

This plot can be formatted in a number of different ways.

Bar Chart

The default view of the upper part of the UpSet plot is the stacked Bar Chart, shown above, summarizing the proportion of treatments. Choose Stacked Bar to produce this view.

Box Plot

Choose Box Plot to produce side-by-side Box Plots, summarizing the Number of Days of Overlap for Occurrence Groups, as shown below.

Range Bar

Choose Range Bar to produce a range bar plot, formatted to appear like a confidence interval, that summarizes the median value as a symbol with low and high interval values represented by the minimum and maximum observed values, respectively, shown below.

Interquartile Range Bar

Choose Interquartile Range Bar to produce a range bar plot, formatted to appear like a confidence interval, that summarizes the median value as a symbol with low and high interval values represented by the first quartile and third quartile values, respectively, shown below.

Term of Interest

The Term of Interest list option makes it straightforward to select all pairs in the data filter that contain a particular term. Note: It is important to clear the data filter of current selections since selecting a Term of Interest will respect current filter selections.

Frequencies by Treatment

Check this box to display frequencies by treatment for both the patients in occurrence groups and patients with occurrences.

Report Filter

The Report filter includes a number of important columns from the Number of Days of Overlap data table by default.

Domain Pair lists the domains from where each Term of Interest is derived, and currently includes adverse events (AE), concomitant medications (CM), or deaths (ADSL). This is the most straightforward way to look at overlapping pairs of medications or adverse events or all medications being taken when death occurred.

Pair is the set of Terms of Interest where the first term always comes before the second term alphabetically. This is a useful way to select individual pairs of interest. As described above, all pairs that contain a single term can be selected from the Term of Interest list box.

Overall Frequency of Patients in Occurrence Group is the total number of patients across all treatments for the Occurrence Group. Essentially, this is the sample size for the bar chart present in the Overall Frequency of Patients in Occurrence Group vertical axis and Occurrence Group horizontal axis.

Maximum Difference in Treatment Frequencies is the difference in the maximum and minimum treatment sample size for an Occurrence Group. Essentially, this is the difference derived for the bar chart present in the Overall Frequency of Patients in Occurrence Group vertical axis and Occurrence Group horizontal axis when Frequencies by Treatment is checked.

Maximum Difference in Treatment Median Days is the difference in the maximum and minimum treatment median days for the Number of Days of Overlap.

Refer to Data Filter for more information.

Note: Filter specifications are reapplied when any widget options are changed.

Action Buttons

Action buttons provide you with an easy way to drill down into your data. The following action buttons are generated by this report:

• Click to reset all report options to default settings.
• Click to view the associated data tables. Refer to Show Tables for more information.
• Click to generate a standardized PDF- or RTF-formatted report that contains the plots and charts of selected sections.
• Click to generate a JMP Live report. Refer to Create Live Report for more information.
• Click to take notes and store them in a central location. Refer to Add Notes for more information.
• Click to read user-generated notes. Refer to View Notes for more information.

Default Settings

Refer to Set Study Preferences for default Subject Level settings.

References

Mallet S. (2023). Interactive Safety Graphics for Regulatory Decision Making: Opportunities and Challenges. PhUSE Webinar.

Ballarini NM, et al. (2020). A critical review of graphics for subgroup analyses in clinical trials. Pharmaceutical Statistics 19: 541–560.