1. A novel, data-driven conceptualization of Critical LVOTO based on baseline echocardiograms
CHSS Fall Work Weekend
November 18, 2016
James M. Meza, MD and Brian W. McCrindle, MD, MPH (Study PI) for the LVOTO Baseline Echo Working Group

2. Overview Background, Rationale, Hypothesis
Cluster Analysis – Methods and Results
Defining the groups – Methods and Results
Differentiating characteristics
Group characteristics
Outliers
Discussion, Interpretation, and Clinical Relevance

3. Traditional Classification
Derived from morphologic analysis
Qualitative in nature
Current IPCCC classification of HLHS is complex
Association with outcomes and prognostic potential is unclear

4. Echocardiographic diagnosis is sophisticated and ubiquitous
Detailed quantitative and qualitative evaluation of function and morphology possible
CHSS Imaging Core Lab

5. Rationale and Hypothesis
Research questions
How do these measures relate to one another?
Can infants be grouped based solely on their baseline echocardiographic characteristics, both quantitative & qualitative?
Hypothesis
Novel groups of similar infants with greater clinical relevance can be identified using baseline echocardiographic quantitative and qualitative morphologic and functional characteristics

6. Patient Source CHSS Critical LVOTO Registry Inclusion criteria
Neonate ≤ age 30 days at admission to a CHSS institution
2005 onward
Concordant AV & VA connections
Precludes an adequate systemic cardiac output through the aortic valve
Exclusion criteria
First intervention at a non-CHSS institution
Discordant AV or VA connections
Atrioventricular Septal Defect

7. Echocardiogram available for review
Study Population
Eligible
N=716
Echocardiogram available for review
N=651

8. Echocardiographic Data
Single reviewer
Protocol of 194 variables
Variables for analysis
136 total

9. Classification – Cluster Analysis
Do the variables in the data set tell us anything about the structure of the observations (patients)?
Identifies groups with similar characteristics
NOT which variables differentiate the groups
Hierarchical, unsupervised, non-overlapping, agglomerative
Ward’s method

10. Tree Diagram
N=651 2
N=338 1
N=215 3
N=98

11. Characterizing Groups
Multinomial and logistic regression
Descriptive statistics
Survival analysis

12. Differentiating Factors
Odds Ratio
P value
Group 1
Aortic atresia
0.2
0.01
LV end diastolic area (cm2)
0.03
<
Group 2
3.9
83% concordant if perform classification analysis
Group 3 = reference

13. Distribution of AVA
87%
11% 8%

14. Distribution of LVEDA
cm2
Median LVEDA
1.05
0.57
1.96

15. 1 vs 2 Probability modeled = membership in Group 2
Classification = 89% concordant
Parameter
Estimate
P value
Odds Ratio
95% CL
Aortic atresia
1.72
<
31.33
Tunnel type subvalvar LVOTO
-1.89
0.02
LV end diastolic endocardial length (cm)
3.5
33.58
Group 1
Group 2
P value
Aortic atresia
11% (24/215)
87% (294/338)
<
Tunnel type subvalvar LVOTO
15% (33/215)
1% (4/338)
LV end diastolic endocardial length (cm)
2.41
1.60

16. 1 vs 3 Probability modeled= membership in Group 3
Classification = 88% concordant
Parameter
Estimate
P value
Odds Ratio
95% CL
LV hypoplasia
-1.23
<
0.09
LV end diastolic epicardial area (cm2)
-0.93
0.39
Group 1
Group 3
P value
LV hypoplasia
86% (185/215)
9% (9/98)
<
LV end diastolic epicardial area (cm2)
3.42
6.90

17. 2 vs 3 Probability modeled= membership in Group 3
Classification = 97% concordant
Parameter
Estimate
P value
Odds Ratio
95% CL
Mitral valve annular abnormality
-2.28
<
0.01
Apex forming LV
2.58
172.68
Group 2
Group 3
P value
Mitral valve annular abnormality
99% (336/338)
8% (8/98)
<
Apex forming LV
1% (3/338)
95% (93/98)

18. Operative Strategy Differs by Group
Group 1
Group 2
Group 3
P value
First procedure type
<  
Operation
91%
98%
39%
Catheter 9% 2%
61%
First operation
Single Ventricle Palliation
90%
58%
Biventricular repair 1%
42%

19. Survival Differs by Group%

20. How to explain potential “outliers?”

21. Outlier analysis, aortic atresia in Group 1
Group 1, no AA
(N=191)
Group 1, AA
(N=24)
P value
LV end diastolic area
2.04
1.35
0.0009
LV end diastolic epicardial area
3.53
3.64
0.66
Mitral valve annular abnormality
82% (157/191)
92% (22/24)
0.38
Apex forming LV
23% (43/191)
4% (1/24)
0.03
LV hypoplasia
84% (161/191)
100% (24/24)
Tunnel type subvalvar LVOTO
14% (27/191)
25% (6/24)
0.22
Retrograde flow in PDA
5% (9/191)
29% (7/24)
<
Death
28% (45/191)
26% (14/24)
0.86

22. Outlier analysis, mitral atresia in Group 1
Group 1, no MA
(N=194)
Group 1, MA
(N=21)
P value
LV end diastolic area
2.07
0.97
<
Mitral valve annular abnormality
81% (158/194)
100%
0.03
Apex forming LV
22% (43/194)
5% (1/21)
0.08
LV hypoplasia
85% (164/194)
0.05
Tunnel type subvalvar LVOTO
16% (31/194)
10% (2/21)
0.75
First intervention
0.23
Catheter-based
10% 0%
Operation
90%
First operation type
0.17
AVR 1%
Norwood
69%
95%
Hybrid
19% 5%
Other
Arch procedure
Death
25% (49/194)
17% (10/21)
0.04
Is the mitral atresia actually just very severe mitral stenosis?

23. Outlier analysis, aortic atresia in Group 3
Group 3, no AA
(N=90)
Group 3, AA
(N=8)
P value
LV end diastolic area
4.6
3.7
0.15
Mitral valve annular abnormality
8% (7/90)
13% (1/8)
0.51
Apex forming LV
96% (86/90)
88% (7/8)
0.35
LV hypoplasia
25% (2/8)
0.16
Tunnel type subvalvar LVOTO
7% (6/90) 0%
1.0
First intervention
<
Catheter-based
67% (60/90)
Operation
33% (30/90)
100%
First operation type
Norwood
33% (10/30)
50% (4/8)
Hybrid
20% (6/30)
Arch procedure
37%(11/30
Yasui
10% (3/30)
Death
13% (12/90)
0.59
Is aortic atresia in this group just really severe aortic stenosis?

24. Outlier Analysis, Aortic stenosis in Group 2
Group 2, no AS
(N=300)
Group 2, AS
(N=38)
P value
LV end diastolic area
0.59
1.09
<
Mitral valve annular abnormality
99% (298/300)
100%
1.0
Apex forming LV
0.3% (1/300)
5% (2/38)
0.03
LV hypoplasia
99% (299/300)
97% (37/38)
0.21
Tunnel type subvalvar LVOTO
0.67% (2/300)
0.06
Retrograde flow in PDA 0%
First intervention
0.51
Catheter-based 2% 3%
Operation
98%
97%
First operation type
0.36
Norwood
81%
73%
Heart transplant 1%
Hybrid
17%
24%
Arch procedure
Death
42% (126/300)
32% (12/38)
0.29

25. Do 4 clusters exist? No Group 2 (“HLHS”) and Group 3 (“AS”) remain
Group 1 breaks into two different groups
Group 1
(N=137)
Group 4
(N=78)
P value
Aortic valve atresia
17% (23/137)
1% (1/78)
<0.0001
LV end diastolic area
1.87
2.14
0.05
Mitral valve annular abnormality
83% (114/137)
83% (65/78)
1.0
Apex forming LV
8% (11/137)
42% (33/78)
First intervention
0.80
Catheter-based
9% (13/137)
8% (9/78)
Operation
91% (124/137)
92% (72/78)
First operation type
AVR 0%
3% (2/72)
Single Ventricle Palliation
98% (122/124)
75% (54/72)
Heart transplant
Other
1% (1/72)
Arch procedures
2% (2/124)
21% (15/72)
Death
30% (41/137)
23% (18/78)
0.34
Six groups also evaluated

26. In summary Data driven classification based on:
LV size (end diastolic area)
Presence or absence of aortic atresia
Groups align with surgical strategy and with mortality
Three groups best differentiate patients

27. Interpreting Group 1 “Multiple levels of left-sided obstruction”
AS/MS end of spectrum
Some LV development
Arch hypoplasia and coarctation common
Most underwent an operation (SVP)
Mortality – middle (27%)
“Multiple levels of left-sided obstruction”

28. Interpreting Group 2 AA/MA or AA/MS Hypoplastic aorta Smallest LVs
Apex-forming RV
Almost all had an operation initially – SVP
Highest mortality (41%)
“True HLHS”

29. Interpreting Group 3 “Isolated AS” Most -no MV abnormality No AA
~80% moderate or severe AS
Apex forming LV
Antegrade flow in ascending aorta and arch
Most had a catheter-based first procedure
Lowest mortality (12%)
“Isolated AS”

30. Clinical Relevance Conceptualization vs. Classification
Categories not new
Concepts now supported by data
Brings management ideas into alignment with classification
May relate to underlying etiology

31. Next steps
Develop method to classify infants into these groups, incorporating clinical data

32. THANK YOU