Co-occurrence

The Co-occurrence report enables users to explore all pairs of occurrences (adverse events (AE), concomitant medications (CM), deaths) that happen simultaneously within a patient, overlapping in time, and generate an estimate of that overlap in the number of days. Further, users can compare the overlap of occurrences to the marginal frequencies where occurrences happen individually. Further, 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 considers occurrences such as adverse events from the AE domain, concomitant medications from the CM domain, or deaths based on the presence of a death date in either DM or ADSL.

Unlike the Nearby Occurrences report that expects the user to identify reference occurrences of interest to explore other nearby occurrences that appear within a user-defined time window, Co-occurrence looks for the overlap of all possible pairs of occurrences according to the Term of Interest and determines the length of time these occurrence pairs take place within each patient. Nearby Occurrences is more appropriate to examine specific terms of interest, while Co-occurrence 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 joining individual records to each other, two or more (possibly overlapping) periods of Terms of Interest (say, phenobarbital and dexamethasone) may be identified in the study. However, no attempt to identify and distinguish distinct periods of overlap is currently being made. The Number of Days of Overlap is the frequency of unique study days where both Terms of Interest in an Occurrence Group (currently just pairs) are observed together.

No attempt is being made to assess overlap with respect to the time of day. If the Terms of Interest occur on the same day, they are considered to overlap with each other.

In practice, missing dates for deaths and AEs are likely not to occur. However, medications for chronic disease may have unknown starts dates (indicating the medication was started long in the past) or unknown end dates (implying the drug is still being used to manage disease). While JMP Clinical makes every effort to impute partial dates according to pre-defined rules, in some instances missing dates may still occur. When start or end dates are missing entirely, these will be imputed using the earliest/latest date according to the following rules, assessing the presence of variables in order:

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Start date: Enrollment date (ENRLDT), informed consent date (RFICDT), earliest visit start date (JMPC_ASTDT)

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End date: End of study date (EOSDT), end of participation date (RFPENDT), most recent of visit end date (JMPC_AENDT) or disposition event dates (JMPC_ASTDT).

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

For all studies, occurrences are classified according to the treatment arm; this includes the set of treatments for crossover or multi-treatment studies. Further potential enhancements of the Co-occurrence report could assess the overlap of pairs of Terms of Interest in conjunction with the treatment received (even no treatment) on a given study day.

Usage and Interpretation

The primary output consists of an UpSet Plot which has several important areas of focus. UpSet plots are used to communicate the frequency of subgroups produced according to one or more factors compared to the marginal frequencies of considering each factor alone.

Example 1: Default Settings

Running Co-occurance for Nicardipine using default settings to demonstrate usage and interpretation of results. The Upset plot is shown in Figure 1.

Figure 1: UpSet Plot

Features of the UpSet plot are listed below:

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The vertical and horizontal axes are ordered according to these frequencies so that the further right (or down) in the plot, the smaller the frequency.

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The line and dots area of the figure illustrate the connections between Terms of Interest along the Occurrence vertical axis and the Occurrence Group horizontal axis.

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The Bar Chart present in the Overall Frequency of Patients in Occurrence Group vertical axis and Occurrence Group horizontal axis presents the frequency of each Occurrence Group, which for now is limited to pairs of occurrences. This bar chart is presented in decreasing frequency, left to right.

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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 decreasing frequency, top to bottom.

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The top area of the figure, within the Proportion of Treatment vertical axis and the Occurrence horizontal axis is a stacked bar chart which 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 to 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 overlapping in time within patient. A patient could take both phenobarbital and dexamethasone, but if there is no overlap on the same study days, it is not counted towards the 470 patients with phenobarbital and dexamethasone.

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

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A subset will not have dexamethasone at all.

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The remaining patients will have taken some dexamethasone, but not on the same days as phenobarbital.

Similarly, of the 129 patients that had dexamethasone with no overlapping phenobarbital:

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A subset will not have phenobarbital at all.

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The remaining patients will have taken some phenobarbital, but not on the same days as dexamethasone.

Of these 470 pairs, 0.48 and 0.52 of them occur within patients on 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 with sample sizes for each treatment (Figure 3). Although filtering may be needed to view treatment-specific sample sizes, we can observe that 230 and 240 patients on Nicardipine or Placebo, respectively, had the “Dexamethasone, Phenobarbital” pair.

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

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 column name are across all treatments, while the others are specific to the treatment listed in a particular row.

Options

Data - Adverse Events

Term Level

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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

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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.

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A preferred term is restricted to a single medical concept.

Verbatim Term (VT)

AETERM in AE

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Select this option to use the term as listed in the adverse event term variable.

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Verbatim terms are identified by values within the reported term (AETERM) variable of AE.sas7bdat data set.

Body System

AEBODSYS in AE

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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

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A superordinate descriptor for multiple preferred terms (PTs).

High(er) Level Group Term (HLGT)

AEHLGT in AE

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A superordinate descriptor for multiple higher level terms (HLTs)

Standard MedDRA Query

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

Primary System Organ Class (SOC)

AESOC in AE

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Uses Primary System Organ Class level of adverse events as categories.

Lowest Level Term (LLT)

AELLT in AE

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Uses Lowest Level Term level of adverse events as categories.

Body System or Organ Class

AEBODSYS in AE

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Uses Body System or Organ Class level of adverse events as categories.

Dictionary-Derived Term

AEDECOD in AE

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Uses Dictionary-Derived Term level of adverse events as categories.

Reported Term for the Adverse Event

AETERM in AE

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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)

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Uses Reported Name level of intervention as categories.

Standardized Name

either CMDECOD (for Concomitant Medications) or SUDECOD (for Substance Use)

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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

Event Type

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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

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Include all events.

Pre treatment events

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Include events that occur before dosing for treated subjects.

Treatment emergent adverse events

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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

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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

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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

Data - Concomitant Medications

Term Level

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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

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Verbatim medication name that is either preprinted or collected on a CRF.

Standardized Medication Name

CMDECOD in CM

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Standardized or dictionary-derived text description of CMTRT. Equivalent to the generic drug name in WHO Drug.

Category for Medication

CMCAT in CM

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Used to define a category of medications/treatments.

Intervention Type

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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

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Include all interventions.

Pre treatment interventions

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

Treatment emergent interventions

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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

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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

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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.