Ejection Fraction Endpoint

Questions:

Is screening considered visit 1, or is it to include the subject into the study? SDTM team agreed to change to VISIT 1 instead of SCREENING.
Are these Real World Evidence (RWE) studies only or clinical trials?
Should both endpoints be shown in one efficacy dataset or two? I will be showing 3 datasets.
What is a good surface area to use for the child subject?
Should i use Male and 6 years? please advise.

In this section, example analysis datasets are shown for the following endpoints:

Percent change in ejection fraction for a period of 1 year
Decline in ejection fraction for a period of 1 year, grouped by a decline greater than 10.0%
Percent change in NTproBNP for a period of 1 year

Source Data

The SDTM examples used as the source data are from Section 2.1, Basic CMR Tests - Systolic Function. The CV dataset contains 16 rows, 1-8 for visit 1 and 9-16 for visit 6. Of these rows, the ones where CVTESTCD = "LVEF_C" and "RVEF_C" were used for analysis. In the LB dataset, the records where LBTESTCD = "BNPPRONT" were used to compute the percentage change over time, then added as a potential covariate in each row for the last analysis. The SDTM datasets were merged with a Subject Level Analysis Dataset (ADSL) dataset to record the demographics, treatments and other appropriate variables for analysis.

ADaM Datasets

The tables below show the example analysis datasets and unique parameters for this endpoint. In this example, only some of the required variables, plus important stratification variables from ADSL, are shown for illustrative purposes. For example, body surface area at baseline (BSABL) was computed for baseline records in ADSL. However, since the subjects are children, the body surface area changes over time. Therefore, it would probably be necessary to have a separate dataset to represent this over time.

Analysis Datasets

Dataset Name	Dataset Description	Class of Dataset	Structure	Location	Keys	Documentation
ADSL	Subject-Level Analysis Dataset	SUBJECT LEVEL ANALYSIS DATASET	One record per subject	adsl.xpt	USUBJID	ADaMIG
ADCVNTP	Cardiac Ejection Fraction and NTproBNP Analysis Dataset	BASIC DATA STRUCTURE	One record per subject per analysis visit per parameter	adcvntp.xpt	USUBJID, AVISITN, PARAMN	Analysis Dataset

ADSL Analysis Dataset

The ADSL includes demographics, treatment groups, study dates and stratification variables. For this example, the ADSL is not shown other than as a source for standard ADaM variables. See Section 2.3.1 of the ADaMIG v1.3 for additional information.

ADCVNTP Analysis Dataset

The ADCVNTP dataset is a subset of the Laboratory Results (LB) SDTM dataset, for which LBTESTCD is equal to "BNPPRONT". In this case, many lab draws may be conducted throughout the year, but only those linked to a specific visit are included. By subsetting the LB dataset with 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.

Parameter Value List - ADCVNTP [ADCVNTP]

Dataset	Variable	Where	Type	Origin	Derivation/Comment
ADCVNTP	AVAL	PARAMCD = "LVEFC"	Num	Predecessor	Set to CV.CVSTRESN where CV.CVTESTCD = "LVEF_C"
ADCVNTP	AVAL	PARAMCD = "RVEFC"	Num	Predecessor	Set to CV.CVSTRESN where CV.CVTESTCD = "RVEF_C"
ADCVNTP	AVAL	PARAMCD = "BNPPRONT"	Num	Predecessor	Set to LB.LBSTRESN where LB.LBTESTCD = "BNPPRONT"

The subsequent section provides the data structures for the example ADaM datasets. In this example, columns for derived variables BASE, CHG, PCHG and CHGCAT1 have been added to facilitate analyses of the efficacy endpoints. Specifically, example demographic data for ADSL were created for an 8 year old male. Also, a custom variable for BSA at baseline (BSABASE) was added from ADSL.

ADCVNTP Variable Metadata

Variable Name	Variable Label	Type	Codelist/Controlled Terms/Format	Source	Derivation/Comment
STUDYID	Study Identifier	Char		CV.STUDYID
USUBJID	Unique Subject Identifier	Char		CV.USUBJID	Select for records with RE data.
ASEQ	Analysis Sequence Number	Num		CV.CVSEQ	Number records 1 to n after sorting by keys.
BSABASE	Body Surface Area (m2) at Baseline	Num		ADSL.BSABASE	Compute in ADSL where VS.VSTESTCD = "BSA".
PARAM	Parameter	Char	Left Ventricular Ejection Fraction, Calculated (%); Right Ventricular Ejection Fraction, Calculated (%); N-Terminal ProB-type Natriuretic Peptide (pg/mL)		For tests from CV, set to the values of CV.CVTEST plus CV.CVTESTU with spaces and parentheses as shown. For tests from LB, set to the value of LB.LBTEST plus LB.LBTESTU with spaces and parentheses as shown.
PARAMCD	Parameter Code	Char	LVEFC; RVEFC; BNPPRONT		If CV.CVTESTCD = "LVEF_C" then PARAMCD = "LVEFC" If CV.CVTESTCD = "RVEF_C" then PARAMCD = "RVEFC" If LB.LBTESTDC = "BNPPRONT" then PARAMCD = "BNPPRONT" Note: for this example dataset, select the records where the test values shown above are included.
PARAMN	Parameter (N)	Num			Number PARAMCD as follows: LVEFC = "1" RVEFC = "2" BNPPRONT = "3"
AVAL	Analysis Value	Num			See Parameter Value List
AVISIT	Analysis Visit	Char			If CV.VISIT = "VISIT 1" then AVISIT = "Visit 1 (Baseline)" Else if CV.VISIT = "VISIT 6" then AVISIT = "Visit 6 (1 Year)"
AVISITN	Analysis Visit (N)	Num			Set to value of CV.VISITNUM or LB.VISITNUM
VISIT	Visit	Num		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 = 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 copying the value of BASE in the baseline record by USUBJID and ADT. (Or by AVISIT if ADT varies for labs, where windowing is applied to select record closest to the visit)
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 >=10.0; Decline < 10.0; Increase		Categorize the value of CHG for Left Ventricular Ejection Fraction, and Calculated (%) (LVEFC) and for Right Ventricular Ejection Fraction, Calculated (%) (RVEFC)
CHGCAT2	Change from Baseline Category 2	Chart			Categorize the value of CHG for N-Terminal ProB-type Natriuretic Peptide (pg/mL) (BNPPRONT)
TRT01P	Planned Treatment for Period 01	Char	Treatment A	ADSL.TRT01P	For this example we are using "Treatment A". In a Real World Evidence study this could be non-treatment related, e.g. "Group A".
ITTFL	Intent-To-Treat Population Flag	Char	Y; N	ADSL.ITTFL
AGE	Age	Num		ADSL.AGE
AGEU	Age Units	Char	(AGEU)	ADSL.AGEU
SEX	Sex	Char	(SEX)	ADSL.SEX
SRCDOM	Source Data	Char	CV; LB		Set to the SDTM domain name 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.

Example 1

This example dataset shows the findings and additional analysis variables associated with:

Left Ventricular Ejection Fraction, Calculated (%)
Right Ventricular Ejection Fraction, Calculated (%)
N-Terminal ProB-type Natriuretic Peptide (pg/mL)

Rows 1-2:	Show the baseline CMR ejection fraction measurements for participant 101 at VISIT 1.
Row 3:	Shows the baseline NTProbTest for participant 101 at VISIT 1.
Rows 4-5:	Show the CMR ejection fraction measurements for participant 101 at VISIT 6.
Row 6:	Shows the NTProbTest for participant 101 at VISIT 6.

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adcvntp.xpt

Row	STUDYID	USUBJID	ASEQ	BSABASE	PARAM	PARAMCD	PARAMN	AVAL	AVISIT	AVISITN	VISIT	ADT	ABLFL	BASE	CHG	PCHG	CHGCAT1	TRT01P	ITTFL	AGE	AGEU	SEX	SRCDOM	SRCSEQ
1	DMD-EFLGE	DMD-EFLGE-101	1	0.65	Left Ventricular Ejection Fraction, Calculated (%)	LVEFC	1	67	Visit 1 (Month 1)	1	VISIT 1	16May2022	Y	67				Treatment A	Y	8	YEARS	M	CV	3
2	DMD-EFLGE	DMD-EFLGE-101	2	0.65	Right Ventricular Ejection Fraction, Calculated (%)	RVEFC	2	74	Visit 1 (Month 1)	1	VISIT 1	16May2022	Y	74				Treatment A	Y	8	YEARS	M	CV	7
3	DMD-EFLGE	DMD-EFLGE-101	3	0.65	N-Terminal ProB-type Natriuretic Peptide (IU/L)	BNPPRONT	3	40	Visit 1 (Baseline)	1	VISIT 1	16May2022	Y	40				Treatment A	Y	8	YEARS	M	LB	1
4	DMD-EFLGE	DMD-EFLGE-101	4	0.65	Left Ventricular Ejection Fraction, Calculated (%)	LVEFC	1	60	Visit 6 (Month 12)	6	VISIT 6	01Jun2023		67	-7	-10.447761	Decline >=10.0	Treatment A	Y	8	YEARS	M	CV	11
5	DMD-EFLGE	DMD-EFLGE-101	5	0.65	Right Ventricular Ejection Fraction, Calculated (%)	RVEFC	2	61	Visit 6 (Month 12)	6	VISIT 6	01Jun2023		74	-13	-17.567568	Decline >=10.0	Treatment A	Y	8	YEARS	M	CV	15
6	DMD-EFLGE	DMD-EFLGE-101	6	0.65	N-Terminal ProB-type Natriuretic Peptide (IU/L)	BNPPRONT	3	900	Visit 6 (Month 12)	6	VISIT 6	1Jun2023		40	860	2,150		Treatment A	Y	8	YEARS	M	LB	2

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Dataset Wrapper Debug Message

Please add a row column to your dataset.

Example 2

The dataset above can also be set up to provide multivariate analyses by taking the lab tests of interest, transposing and merging with the ADCVNTPP dataset. In that case, the records from LB are not needed as a row.

The variables transposed and merged to the rows created from CV are:

Dataset	Value	Where	Variable	Variable Label
ADCVNTP	AVAL	PARAMCD = "BNPPRONT"	BNPPRONT	N-Terminal ProB-type Natriuretic Peptide (IU/L)
ADCVNTP	CHG	PARAMCD = "BNPPRONT"	BNPCHG	N-Term ProB-type N Pep Change Category

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adcvntp.xpt

Row	STUDYID	USUBJID	ASEQ	BSABASE	BNPPRONT	BNPCHG	PARAM	PARAMCD	PARAMN	AVAL	AVISIT	AVISITN	VISIT	ADT	ABLFL	BASE	CHG	PCHG	TRT01P	ITTFL	AGE	AGEU	SEX	SRCDOM	SRCSEQ
1	DMD-EFLGE	DMD-EFLGE-101	1	0.65	40		Left Ventricular Ejection Fraction, Calculated (%)	LVEFC	1	67	Visit 1 (Month 1)	1	VISIT 1	16MAY2022	Y	67			Treatment A	Y	8	YEARS	M	CV	3
2	DMD-EFLGE	DMD-EFLGE-101	2	0.65	40		Right Ventricular Ejection Fraction, Calculated (%)	RVEFC	2	74	Visit 1 (Month 1)	1	VISIT 1	16MAY2022	Y	74			Treatment A	Y	8	YEARS	M	CV	7
3	DMD-EFLGE	DMD-EFLGE-101	3	0.65	900	2150	Left Ventricular Ejection Fraction, Calculated (%)	LVEFC	1	60	Visit 6 (Month 12)	6	VISIT 6	01JUN2023		67	-7	-10.447761	Treatment A	Y	8	YEARS	M	CV	11
4	DMD-EFLGE	DMD-EFLGE-101	4	0.65	900	2150	Right Ventricular Ejection Fraction, Calculated (%)	RVEFC	2	61	Visit 6 (Month 12)	6	VISIT 6	01JUN2023		74	-13	-17.567568	Treatment A	Y	8	YEARS	M	CV	15

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ADCVEF Analysis Dataset

The ADCVEF dataset includes tests pertinent to this analysis, those for which CVTESTCD is equal to "LVEF_C" or "RVEF_C". The relationship dataset RELREC illustrates the relationship between datasets.

ADCVMRI Analysis Dataset

ADCMRI is an efficacy analysis dataset with only a few records for more complex modeling of changes in ejection fraction, plus the ProB-type test results. It is an ADaM Basic Data Structure (BDS) dataset, with additional variables added from ADCVEF.

Example Analysis Results Metadata (ARM) Tables

This is an example ARM table for the selected endpoint. Other endpoints can be represented in the same way describing the variables and procedures used. For more details on ARM, see the ADaMIG and the ARM implementation in Define-XML (available at https://www.cdisc.org/standards/foundational/define-xml/).

Display	Table 14.xx.xx Percent change in NTproBNP over a period of time (yearly)
Analysis Result	Comparison of Percent Change of NTproBNP for the Treatment Groups Over Time (quarterly or yearly)
Analysis Variables(s)	PCHG
Analysis Reason	Primary efficacy endpoint as prespecified in the SAP
Analysis Purpose	Primary outcome measure
Data References (incl. selection criteria)	PARAMCD = "BNPPRONT" Where ITTFL = "Y"
Documentation	The mixed model using lsmeans to compare treatment groups
Programming Statements (Add programming language statements here: SAS, R, etc.)	PROC MIXED DATA=ADCVNTPR; WHERE PARAMCD = "BNPPRONT"; CLASS STUYDID TRT01P AVISITN; MODEL PCHG=AVISITNTRT01P/Solution; RANDOM INTERCEPT / SUBJECT=STUYDID TYPE=UN; LSMEANS TRT01PAVISITN/ CL PDIFF; RUN;

Display	Table 14.xx.xx Percent Change in Left Ventricular Ejection Fraction Over Time
Analysis Result	Comparison of Percent Change of Ejection Fraction for the Treatment Groups Over Time
Analysis Variables(s)	PCHG
Analysis Reason	Primary efficacy endpoint as prespecified in the SAP
Analysis Purpose	Primary outcome measure
Data References (incl. selection criteria)	PARAMCD = "LVEFC" Where ITTFL = "Y"
Documentation	The mixed model using lsmeans to compare treatment groups
Programming Statements (Add programming language statements here: SAS, R, etc.)	PROC MIXED DATA=ADCVNTP; CLASS STUYDID TRT01P AVISITN; MODEL PCHG=AVISITNTRT01P/Solution; RANDOM INTERCEPT / SUBJECT=STUYDID TYPE=UN; LSMEANS TRT01PAVISITN/ CL PDIFF; RUN;

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