1     General Considerations

This section describes the implementation of the analysis dataset for QRS instruments as based on the Basic Data Structure (BDS) described in the Analysis Data Model Implementation Guide (ADaMIG). The ADaMIG can be found on the CDISC website at https://www.cdisc.org/standards/foundational/adam. The BDS was chosen as the model for analysis datasets of QRS instruments because it supports a wide variety of analyses, including summaries of total score by timepoint as well as change from baseline by timepoint. This data structure allows the ADaM variables PARAM and PARAMCD to come directly from Study Data Tabulation Model (SDTM) variables RS.RSTEST and RS.RSTESTCD, respectively, for individually captured questions, thus ensuring traceability between SDTM and ADaM data. If other analyses are required that are not supported by the BDS, then consideration would be needed as to the appropriate structure. Analysis requirements always drive the design of the analysis datasets.

This ADaM supplement is based on the Acute Physiology and Chronic Health Evaluation II (APACHE II) Clinical Classification Supplement Version 2.0 to the SDTM Implementation Guide for Human Clinical Trials (SDTMIG). 

Note that source SDTM score values may not be suitable for analysis because the values may need to be imputed or transformed. In addition, recalculation of collected values may be needed per analysis rules. In these cases, the derivation of AVAL may not be a simple copying of RS.RSSTRESN. 

These specific analysis implementation details for the APACHE II are meant to be used in conjunction with ADaMIG. All completed questionnaires, ratings, and scales documentation can be found on the CDISC website at: https://www.cdisc.org/foundational/qrs.

1.1   Representations and Warranties, Limitations of Liability, and Disclaimers

This document is a supplement to the ADaMIG and is covered under Appendix C of that document, which describes representations, warranties, limitations of liability, and disclaimers. Please see Appendix C of the ADaMIG for a complete version of this material.

CDISC does not endorse any QRS instrument and does not specify how to conduct clinical assessments, protocols, or analyses. CDISC disclaims any liability for your use of this material.

Include this line only for supplements that the US FDA will be reviewing: Although the United States Food and Drug Administration (US FDA) has provided input with regard to this supplement, this input does not constitute US FDA endorsement of any particular instrument.  

1.2   Copyright Status

CDISC believes this instrument to be in the public domain, but you should perform your own assessment. CDISC has included the APACHE II in the CDISC library of QRS data standards supplements. There may be many versions of this instrument in the public domain or copyrighted. CDISC has chosen to use the version attached to the QRS supplement to the SDTMIG, and the QRS supplement to the ADaMIG is based on the same version.

Note: CDISC Controlled Terminology is maintained by National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS). The most recent versions of the SDTM and ADaM controlled terminologies should be accessed through the CDISC website (https://www.cdisc.org/standards/terminology).

1.3   Known Issues

The Acute Physiology and Chronic Health Evaluation (APACHE II) is a severity of disease measurement and mortality estimation tool for adult patients applied within 24 hours of admission to an intensive care unit (ICU). The instrument consists of individual items that are summed up to create a total score. This instrument is generally collected once at Screening/Baseline and used as a predictor of mortality rather than an outcome measure. The total score is normally collected as part of the instrument with no instructions provided for handling missing data. In the majority of cases, where APACHE II is only assessed once and the collected total score used as a baseline covariate, the SDTM RS domain may be sufficient to support the analysis requirements, as a variable in ADSL copied directly from a result/value in SDTM.

2     Rules and References

The primary source used in the development of this supplement is Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Critical Care Medicine 1985; 13(10):818–29. 

All links are valid and referenced information is current as of the date of this ADaMIG QRS supplement. This supplement does not make recommendations for the handling of missing data or adoption of imputation methods.

3     Scoring Software

There is no known publicly available scoring software as of the date of this ADaMIG QRS supplement.

4     Introduction to the Instrument   

The APACHE II is a severity-of-disease classification system that uses a point score based on the initial values of 12 routine physiologic measurements, age, and previous health status. Scores range from 0 to 71 and higher scores correspond to more severe disease and a higher risk of death. The composite score is based on findings represented in other SDTM domains such as Laboratory Test Results (LB) and Vital Signs (VS).

5     Key Data Checks

The computed total score consists of integer values ranging from 0 to 71. The classification system consists of 11 physiology measures based on a numeric rating scale (0-4) where 0 reflects values within the normal range and an increase in the numeric rating scale represents an increase in the abnormality of the physiology measure in either the high or low direction. The final physiology measure, the Glasgow Coma Score (GCS), is reversed; so that lower scores indicate mild or no head injury and higher scores represent more severe head injury and range from (0-12). Chronological age is divided into disjoint categories and assigned values of (0, 2, 3, 5, 6). For patients with a history of severe organ system insufficiency or who are immunocompromised, a numeric rating of 2 or 5 is assigned for chronic health points, where 2 is assigned “for elective postoperative patients” and 5 is assigned “for nonoperative or emergency postoperative patients”.

6     Example

6.1   Background

Analyses based on ADaM datasets may vary depending on the sponsor, therapeutic area, and the needs of regulatory authorities in their decision-making processes. This fictional example is provided for illustrative purposes only. The ADaM dataset describing the analysis results from an instrument is based on the protocol and statistical analysis plan (SAP) for the individual study.

The example dataset described here is intended to support a variety of analyses, ranging from simple univariate summary statistics on the actual total scores to other types of by-visit and repeated-measure analyses. For that reason, standard ADaM BDS variables such as AVAL (analysis value) have been included in the example. In addition, although not illustrated in the example, the APACHE II total score can be divided into categories (e.g., <17 >=17) reflecting disease severity or risk of death, and the frequency of subjects reporting in each category may be generated or used for analysis.

In the example presented here, it is assumed that the final APACHE II analysis dataset (ADAPCH) contains all of the original records, plus a record for the computed total acute physiology score and a record for the computed total APACHE II for each patient and assessment timepoint. The date of the assessment—and time of the assessment, if collected—should also be included in the dataset. For traceability, raw item-level responses from the SDTM RS.RSORRES variable, stored separately from the analysis variable AVAL, are included. Derivation type (DTYPE) should be used to clearly indicate records where missing values have been imputed using sponsor-defined imputation methods. If useful for analysis, a summary analysis dataset which includes only the computed total score records may also be created.

6.2   Example Analysis Dataset, Variable and Value-level Metadata

The ADAPCH Dataset Metadata table shows an example of how the APACHE II may be implemented in ADaM. The dataset metadata is a recommendation for the dataset name, label, structure, and keys. These can be modified for sponsor-specific standards and analyses. 

The ADAPCH Variable Metadata table contains an example of analysis variable metadata for a subset of possible variables available for the APACHE II. Example value-level metadata are found in the Parameter Value Level List - ADAPCH [AVAL] metadata table. The ADAPCH Variable Metadata table does not include all of the possible variables that may be present in the Subject-Level Analysis Dataset (ADSL) and copied to the BDS structure analysis dataset, with the exception of the required STUDYID and USUBJID. For a complete list of available ADSL variables, consult the ADaMIG. Some ADSL variables (e.g., REGION1) were included in this example for stratification, and are not required. Additional covariates or other variables may be added as needed for analysis. Common BDS variables such as BASE and CHG have been omitted from the example as the majority analyses of APACHE II do not use these variables. There is no specific ordering of variables recommended in this supplement. The SDTM variables were placed next to the corresponding derived ADaM variables for illustration purposes only. 

The following SDTM variables can be copied into the corresponding equivalent ADaM variables. Note that the SDTM variable values can be converted to mixed case as needed for analysis purposes.  

All controlled terminology for instruments in both SDTM and ADaM is associated with a specific version of the instrument. When integrating responses from an instrument across studies, it is important to know which version of the instrument was used for each study. When multiple versions of the same instrument exist in an integration, a pooled analysis of responses across different versions can only be performed if determined to be clinically and statistically acceptable. In that case, sponsor-defined terminology, similar to CDISC Controlled Terminology but without the reference to a specific version, should be used for PARAMCD, PARAM and PARCATy.

6.3   Example Analysis Dataset 

The APACHE II Summary Analysis Dataset table shows the terminology and variables for implementing the example analysis dataset for this instrument in the BDS. This specific example is taken from a Phase II, randomized, controlled, open label multi-center study to assess the efficacy and safety of Drug A for the treatment of SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired respiratory function. The primary outcome measure is APACHE II Severity of Disease Score on Day 15 or on the Day of Discharge (Whichever is Earlier). This measure compares Drug A + Standard of Care (SOC) versus the Standard of Care (SOC). 

In this example, the APACHE II score was measured on Day 1 (prior to implementation of treatment), Day 7, and Day 15 or on the day of discharge (whichever was earlier). In the example, as per the SAP, participants who died on Day 15 or earlier were assigned the highest observed APACHE II score of any of the participants at any time during the trial (worst case imputation for deaths). This imputation method is for example purposes only and not meant to be a recommendation nor considered a common practice. Missing data values of the parameters required for the derivation of the APACHE II score were replaced by the last available assessment. Item level imputation, in this example, is handled by the investigators and/or clinicians at the site and is considered source data, already captured in SDTM. The  --LNKID variable can be used to determine the source or input record used to assess that particular physiological item on APACHE II at that time point. SOC included a variety of supportive therapies that ranged from the administration of supplementary oxygen to full intensive care support, alongside the use of antiviral treatment, convalescent plasma, corticosteroids, antibiotics or other agents.

In the example, the SAP specifies that planned collected visits, including baseline measurements, are to be used in analyses and displays of results. In fact, no Unscheduled Visits exist in the source data. If the planned physiology assessment is not done or invalid, the investigator may choose to use a previous or repeat assessment of that parameter as the value at that visit for the scoring of APACHE II. The records for 2 subjects are show in the example datasets. The data for 3 visits is shown for the first subject with no missing data. The data for 1 visit is shown for the second subject, who died before the Day 15 (Day of Discharge) Visit so the APACHE II total score is imputed to the worst case value of any subjects across any timepoints at that visit. Note that the worst case value is not shown in the sample data.

APACHE II Complete Analysis Dataset

The APACHE II Complete Analysis Dataset table shows all of the individual question responses for this example, as well as the computed total Acute Physiology score and the computed total APACHE II score. This example is considered to be the final analysis dataset for submission. Computed total scores can appear after the individual item responses, with appropriate labels for identification.

APACHE II Summary Analysis Dataset

Due to the number of items on the instrument and the fact that only the total APACHE II score records are required for analysis, the separate summary dataset shown in the following example, which contains only the total APACHE II score records, may also be created.  RSSEQ was not included in this example because it would be null for all computed total score records. RSORRES is not shown because only derived total score records are displayed.

7   References

1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Critical Care Medicine 1985; 13(10):818–29. 

End of Document