Measuring left ventricular ejection fraction LVEF regularly can show the rate of decline in left ventricle function for a patient with DMD. Thus it was selected as an example endpoint to measure whether a course of therapy provides a slowing of the progression to heart failure for the patient. The second endpoint chosen, NT-proBNP, is a biomarker that is used to predict or diagnose heart failure.
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The SDTM examples used as the source data are from Section 2.1, Basic Systolic Function. The readings chosen to analyse analyze ejection fraction are the Left Ventricular Ejection Fraction, Cal, with the unit of percent. The example dataset below also shows the Right Ventricular Ejection Fraction, Cal which can be used to confirm the result. The SDTM data are stored in the CV Domaindomain. The example dataset dataset in Section 2.1 shows two 2 visits for subject DMD-EF-01-101. The records for which CVTESTCD = "LVEF_C" and "RVEF_C" were selected for analysis.
The N-Terminal ProB-type Natriuretic Peptide NT-proBNP test is stored in the LB domain. The example dataset in section Section 2.1 shows the test in the example LB dataset where (LBTESTCD = "BNPPRONT"). The lab value was used to compute the percent change over time for the third endpoint and as a potential covariate for the ejection fraction models.
The example Adam Subject-level Analysis (ADSL) dataset draws from the DM dataset for demographics and study dates. It draws from Vital Signs (VS) for height and weight at screening. The VS is also used for height and weight at each visit, which in turn is used to compute Body Surface Area body surface area (BSA), an important measure used in calculations for the basic systolic functions. A flag for Ace Inhibitor Medications angiotensin-converting enzyme (ACE) inhibitor medications was added to the example. The source for this data would be concomitant medications , (CM) or or dosing information (EX, EC), not shown.
Example Analysis Datasets
The following tables below show the analysis dataset metadata and parameters used for this example.
| Definexmltable |
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| Multiple | true |
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| Level | Dataset |
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| Purpose | Analysis |
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|
Dataset Name | Dataset Description | Class of Dataset | Structure | Keys | Documentation | Location |
|---|
ADSL | Subject-Level level Analysis Dataset | SUBJECT LEVEL ANALYSIS DATASET | One record per subject | USUBJID | ADaMIG | adsl.xpt | | ADCVNTP | Cardiac Ejection Fraction and NT-proBNP Analysis Dataset | BASIC DATA STRUCTURE | One record per subject per analysis visit per parameter | USUBJID, AVISITN, PARAMN | | adcvntp.xpt | | ADCVCMR | Cardiovascular CMR Ejection Fraction Analysis Dataset | BASIC DATA STRUCTURE | One record per subject per analysis visit per parameter | USUBJID, AVISITN, PARAMN | | adcvcmr.xpt |
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- Analysis age (AAGE) was included to provide age with more precision.
- A flag indicating the use of ACE inhibitors (ACEINHFL) is shown with example derivation from the CM dataset.
- Body surface area at screening (BSASC) was derived from the VS dataset using height and weight at the screening visit. There are many possible calculations for BSA; for this example, the Du Bois method was used.[11] was used. Note that the screening visit and visit 1 occurred at the same time in this example.
| Definexmltable |
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| Dataset | ADSL |
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| Level | Variable |
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| Purpose | Analysis |
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| Name | Variable |
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| Variable Name | Variable Label | Type | Codelist/Controlled Terms/Format | Source | Derivation/Comment |
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| STUDYID | Study Identifier | Char |
| DM.STUDYID |
| | USUBJID | Unique Subject Identifier | Char |
| |
| | BRTHDT | Date of Birth | Num | date9. |
| Date portion of DM.BRTHDTC converted to numeric and displayed in a format such as date9.from ISO 8601 format to numeric date.9 | | AAGE | Analysis Age | Num |
|
| Age as screening, computed by DM.RFICDTC - BRTHDTC as continuous variable. Note that some countries do not allow capturing date of birth, so this could be computed by capturing age in years and months on a CRF. | | AGE | Age | Num |
| DM.AGE |
| | AGEU | Age Units | Char | YEARS | DM.AGEU |
| SEX | Sex | Char | (SEX) | DM.SEX |
| RACE | Race | Num | (RACE) | DM.RACE |
| | TRTSDT | Date of First Exposure to Treatment | Num | date9. |
| Date portion of DM.RFSTDTC converted to numeric and displayed in a format such as date9. | | RFICDT | | Num | date9. |
| Date portion of DM.RFICDTC converted to numeric and displayed in a format such as date9. | | DTHDT | | Num | date9. |
| Date portion of DM.RFSTDTC converted to numeric and displayed in a format such as date9. | | DTHFL | | Char | Y | DM.DTHFL |
| | TRT01P | Planned Treatment for Period 01 | Char | Drug A, Drug B |
| Predecessor: DM.ARM. May be changed to lower case or more descriptive term for use in tables and listings. | | TRT01A | Actual Treatment for Period 01 | Char | Drug A, Drug B |
| Predecessor: DM.ACTARM. Note: Actual treatment matches planned treatment unless there is a reason subject does not take planned drug. | ITTFL | Intent-To-Treat Population Flag | Char | Y; N |
| Derive the intent-to-treat population as per the protocol and SAP. | ACEINHFL | ACE Inhibitor Medications Flag | Char | Y; N |
| Select a list of ACE inhibitor medications from concomitant medications (CM) domain as per Statistical Analysis Plan SAP or Protocolprotocol. Set to "Y" if these medications were taken during the study, and "N" if they are absent. Can be used to subset or to exclude the population who took ACE inhibitors. | HEIGHTSC | Height (cm) at Screening | Num |
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| Set to VS.VSSTRESN where VS.VSTESTCD = "HEIGHT" and VISITNUM= 1 (or screening visit for your study). | WEIGHTSC | Weight (kg) at Screening | Num |
|
| Set to VS.VSSTRESN where VS.VSTESTCD = "WEIGHT" and VISITNUM = 1 (or screening visit for your study). | BSASC | Body Surface Area at Screening | Num |
|
| Select where VISITNUM = 1 (or screening visit for your study). Compute from HEIGHT and WEIGHT, using the Du Bois method. BSA = 0.007184 × W0.425 × H0.725 There are multiple methods and the study protocol should describe which one to use for calculating BSA (e.g., Du Bois, Mosteller, Haycock, Gehan & George, Boyd, Fujimoto, Takahira, and Schlich); the study protocol should describe which to use. |
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| Dataset wrap |
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| Dataset2 |
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| | Row | STUDYID | USUBJID | BRTHDT | AAGE | AGE | AGEU | SEX | RACE | TRTSDT | RFICDT | DTHDT | DTHFL | TRT01P | ITTFL | ACEINHFL | HEIGHTSC | WEIGHTSC | BSASC |
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| 1 | DMD-EFLGE | DMD-EF-01-101 | 07FEB2010 | 12.3 | 12 | YEARS | M | BLACK OR AFRICAN AMERICAN | 16JUN2022 | 16JUN2022 |
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| Drug A | Y | Y | 119 | 20 | 0.82 | | 2 | DMD-EFLGE | DMD-EF-01-101 | 01MAY2008 | 14.1 | 14 | YEARS | M | ASIAN | 13JUN2022 | 13JUN2022 |
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| Drug A | Y | Y | 115 | 30 | 0.95 | | 3 | DMD-EFLGE | DMD-EF-01-101 | 10JUL2003 | 19.0 | 19 | YEARS | M | NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 15JUL22022 | 15JUL2022 |
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| Drug B | Y | N | 140 | 45 | 1.30 | | 4 | DMD-EFLGE | DMD-EF-01-101 | 15JAN1999 | 23.7 | 23 | YEARS | M | WHITE | 06SEP2022 | 06SEP2022 | 23NOV2023 | Y | Drug B | Y | Y | 132 | 42 | 1.21 |
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The ADCVNTP includes tests pertinent to analyses. The records from CV (where CVTESTCD = "LVEF_C" and "RVEF_C") and the records from LB (where LBTESTCD = "BNPPRONT") were selected. Many lab draws may occur throughout the year, but only those linked to a specific visit were included. By subsetting the LB dataset by LBLNKID not missing, laboratory data that aligns with CV data can be filtered out and sorted using USUBJID and VISIT. If LBLNKID is not available, a windowing strategy could be used to select the laboratory draw closest to that visit for merging with CV, computed in AVISIT.
In this example, variables BASE, CHG, PCHG, and CHGCAT1 were used to facilitate analyses of the efficacy endpoints.
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| Definexmltable |
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| Dataset | ADCVNTP |
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| Level | Variable |
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| Purpose | Analysis |
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| Name | Variable |
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|
| Variable Name | Variable Label | Type | Codelist/Controlled Terms/Format | Source | Derivation/Comment |
|---|
| STUDYID | Study Identifier | Char |
| CV.STUDYID |
| | USUBJID | Unique Subject Identifier | Char |
| |
| | BRTHDT | Date of Birth | Num | Date9. | ADSL.BRTHDT |
| | AAGE | Analysis Age | Num |
| ADSL.AAGE |
| | AGEU | Age Unit | Char | YEARS | ADSL.AGEU |
| SEX | Sex | Char | (SEX) | DM.SEX |
| RACE | Race | Num | (RACE) | DM.RACE |
| | TRTSDT | Date of First Exposure to Treatment | Num | date9 | ADSL.TRTSDT |
| | TRT01P | Planned Treatment for Period 01 | Char | Drug A; Drug B | ADSL.TRT01P |
| | TRT01A | Actual Treatment for Period 01 | Char | Drug A; Drug B | ADSL.TRT01A |
| ITTFL | Intent-To-Treat Population Flag | Char | Y; N | ADSL.ITTFL | | HEIGHT | Height (cm) | Num |
|
| Set to VS.VSSTRESN where VS.VSTEST = "HEIGHT" by visit. | WEIGHT | Weight (kg) | Num |
|
| Set to VS.VSSTRESN where VS.VSTEST = "WEIGHT" by visit. | | BSA | Body Surface Area (m2) | Num |
|
| Compute from HEIGHT and WEIGHT at each visit, using the Du Bois method. BSA = 0.007184 × W0.425 × H0.725 There are multiple methods and for calculating BSA; the study protocol should describe which one to use (e.g., Mosteller, Haycock, Gehan & George, Boyd, Fujimoto, Takahira, and Schlich). | ACEINHFL | ACE Inhibitor Medications Flag | Char | Y; N | ADSL.ACEINHFL |
| | PARAM | Parameter | Char | Left Ventricular Ejection Fraction, Cal (%); Right Ventricular Ejection Fraction, Cal (%); N-Terminal ProB-type Natriuretic Peptide (ng/L) | CV.CVTEST LB.LBTEST |
| | PARAMCD | Parameter Code | Char | LVEF_C; RVEF_C; BNPPRONT | CV.CVTESTCD LB.LBTESTCD |
| | PARAMN | Parameter (N) | Num |
|
| Number PARAMCD as follows: LVEF_C = "1" RVEF_C = "2" BNPPRONT = "3" | | AVAL | Analysis Value | Num |
|
| See Parameter Value Metadata | | AVISIT | Analysis Visit | Char | Visit 1 (Baseline); Visit 6 (1 Year) |
| If CV.VISIT = "VISIT 1" then AVISIT = "Visit 1 (Baseline)". If CV.VISIT = "VISIT 6" then AVISIT = "Visit 6 (1 Year)". | | AVISITN | Analysis Visit (N) | Num | 1; 6 | CV.VISITNUM LB.VISITNUM |
| | VISIT | Visit | Num | VISIT 1; VISIT 6 | CV.VISIT LB.VISIT |
| | ADT | Analysis Date | Num | date9. |
| Date portion of CV.CVDTC or LB.LBDTC converted to numeric and displayed in a format such as date9. | | ABLFL | Baseline Record Flag | Char | Y |
| If CV.VISIT = "VISIT 1" then ABLFL = "Y". | | BASE | Baseline Value | Num |
|
| Set BASE to AVAL from the record for that subject and parameter where ABLFL = "Y". Populate BASE for additional visits by merging the value of BASE in the baseline record by USUBJID and PARAMCD. | | CHG | Change from Baseline | Num |
|
| Compute CHG = AVAL - BASE for that record. Only compute for post-baseline records. | | PCHG | Percent Change from Baseline | Num |
|
| Compute PCHG = (CHG / BASE) * 100. Only compute for post-baseline records. | | CHGCAT1 | Change from Baseline Category 1 | Char | Decline >=5%; Decline <5%; Increase GT 100 ng/L |
| See Parameter Value Metadata | | SRCDOM | Source Data | Char | CV; LB |
| Set to the SDTM domain name that relates to the analysis value. | | SRCVAR | Source Variable | Char |
|
| Set to the SDTM variable that relates to the analysis value. | | SRCSEQ | Source Sequence Number | Num |
| CV.CVSEQ LB.LBSEQ | Set to the SDTM domain sequence number that relates to the analysis value. |
|
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The ADCVMR is an efficacy analysis dataset with only a few records for more complex modeling of changes in ejection fraction, plus the ProBproB-type test results. It is an ADaM Basic Data Structure (BDS) dataset, with additional variables added from ADCVNTP.
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| Definexmltable |
|---|
| Dataset | ADCVCMR |
|---|
| Level | Variable |
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| Purpose | Analysis |
|---|
| Name | Variable |
|---|
|
| Variable Name | Variable Label | Type | Codelist/Controlled Terms/Format | Source | Derivation/Comment |
|---|
| STUDYID | Study Identifier | Char |
| ADCVNTP.STUDYID |
| | USUBJID | Unique Subject Identifier | Char |
| |
| | BRTHDT | Date of Birth | Num | date9. | ADCVNTP.BRTHDT |
| | AAGE | Analysis Age | Num |
| ADCVNTP.AAGE |
| | AGEU | Age Unit | Char | YEARS | ADCVNTPL.AGEU |
| SEX | Sex | Char | (SEX) | ADCVNTPL.SEX |
| RACE | Race | Num | (RACE) | ADCVNTPL.RACE |
| | TRTSDT | Date of First Exposure to Treatment | Num | date9. | ADCVNTP.TRTSDT |
| | TRT01P | Planned Treatment for Period 01 | Char | Drug A; Drug B | ADCVNTP.TRT01P |
| ITTFL | Intent-To-Treat Population Flag | Char | Y; N | ADCVNTP.ITTFL | | | BSA | Body Surface Area (m2) | Num |
| ADCVNTP.BSA |
| ACEINHFL | ACE Inhibitor Medications Flag | Char | Y; N | ADCVNTP.ACEINHFL |
| BNPPRONT |
| Num |
|
| BNPPRONT = AVAL where PARAMCD = ADCVNTP.BNPPRONT, and merge by USUBJID and AVISITN. Note: there There are many ways to add this including transposing the data. | | PARAM | Parameter | Char | Left Ventricular Ejection Fraction, Cal (%); Right Ventricular Ejection Fraction, Cal (%) | ADCVNTP.PARAM | | | PARAMCD | Parameter Code | Char | LVEF_C; RVEF_C | ADCVNTP.PARAMCD |
| | PARAMN | Parameter (N) | Num |
| ADCVNTP.PARAMN |
| | AVAL | Analysis Value | Num |
| ADCVNTP.AVAL |
| | AVISIT | Analysis Visit | Char | Visit 1 (Baseline); Visit 6 (1 Year) | ADCVNTP.AVISIT |
| | AVISITN | Analysis Visit (N) | Num | 1; 6 | ADCVNTP.AVISITN |
| | ADT | Analysis Date | Num | date9. | ADCVNTP.ADT |
| | ABLFL | Baseline Record Flag | Char | Y | ADCVNTP.ABLFL |
| | BASE | Baseline Value | Num |
| ADCVNTP.BASE | | | CHG | Change from Baseline | Num |
| ADCVNTP.CHG |
| | PCHG | Percent Change from Baseline | Num |
| ADCVNTP.PCHG |
| | CHGCAT1 | Change from Baseline Category 1 | Char | Decline >=5.0%; Decline <5.0%; Increase >100 ng/L | ADCVNTP.CHGCAT1 |
|
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