New genomic technologies:
clinical utility and resource planning

Microarray Performed @ SickKids
Currently recommended
as first-tier dx test for
children with
3000
2500
 Developmental delay
Dx yield improved over
traditional methods
 MOHLTC expanded
funding in 2011
 Volume increased

Caseload
 Congenital anomalies
2000
1500
1000
500
0
05/06 06/07 07/08 08/09 09/10 10/11 11/12
Year
(Apr – Mar)
HSR agenda emerging, but under-developed
Without HSR, we may face
 under-evaluated tests
 compromised reimbursement
 inequitable access to the tests
 inadequate health/human resources needed to support the
use of these tests


recent studies on medical management impact
pathogenic CMA results prompt medical
recommendations in 54-94% of cases

Suggestive of utility, outcomes oriented
BUT

Hypothetical decisions, no comparison groups, case
reports
How do pediatric CMA results inform
subsequent medical management
recommendations?
Pediatric CMA Cohort
@ SickKids
(2009-2011)
medical management
recommendations post CMA
medical record review
Total Eligible 2009-2011 (N=1931)
Reportable
24%
Pathogenic
Likely pathogenic
Uncertain
Likely benign
Benign
76%
N=752

Reviewed medical records and MD consult notes via
paper-based and electronic charts
Independent Variables
 Age
 Sex
 CMA result type
 Path, likely path, uncertain,
likely benign, benign
 Phenotype
 Family history
 Ordering MD
Outcome
 New Medical recommendations

Categorized by type:
1) Laboratory testing
2) Specialist consultations
3) Diagnostic imaging
4) Surveillance protocols
5) Investigations for other
family members


Descriptive frequency counts, univariate analysis
Binomial loglink regression to generate relative rates
of new investigations post CMA
2009-11 Cohort (N = 752)
Age
Phenotype
Sex
<12 months
167 (22.2)
1-5 yrs
288 (38.3)
6-10 yrs
122 (16.2)
>10 yrs
175 (23.3)
<2 organ systems
210 (27.9)
2 organ systems
236 (31.4)
3 organ systems
181 (24.1)
>3 organ systems
125 (16.6)
Male
420 (55.9)
Female
332 (44.1)
2009-11 Cohort (N = 752)
CMA result type
Pathogenic
Likely pathogenic
Related Family Hx
Ordering MD
114 (15.2)
72 (9.6)
Uncertain
193 (25.7)
Likely benign
78 (10.4)
Benign
295 (39.2)
Present
159 (21.1)
Absent
593 (78.9)
SickKids
698 (92.8)
Non-SickKids
Geneticist
Non-Geneticist
54 (7.2)
728 (96.8)
24 (3.2)
45%
Overall:
 2508 new investigations recommended

For 548/752 children in cohort (73.0%)
 mean=4.6 investigations per child
Types of Services Recommended
5.0%
5.0%
17.0%
cardiologists,
nephrologists,
neurologists,
developmental
pediatricians, oncologists,
ophthalmologists,
endocrinologists, speech
language, dieticians
41.0%
Specialist Consult
12.0%
Medical Imaging
Lab Test
Surveillance
Family Investigations
% With Any New Recommendations
100
90
80
70
60
50
40
30
20
10
0
*
TOTAL
*
Pathogenic Uncertain,
Likely
Pathogenic
*
Uncertain
Broad
Uncertain
Uncertain,
Likely
Benign
Benign
% With Any New Recommendations
90
80
RR=1.09
(0.99,1.20)
RR=0.80
(0.72,0.89)
70
60
50
40
30
20
10
0
Pathogenic
Uncertain + Likely Path +
Likely Benign
Benign
Among path, 85% received rec, among uncertain 78% received rec,
among benign 62% received rec
% With Any New Recommendations
100
90
80
70
60
50
40
30
20
10
0
*
TOTAL
*
*
Pathogenic
Uncertain,
Uncertain
 Pathogenic

Likely
Pathogenic
Uncertain,
Benign
 Benign

Likely
Benign
% With Any New Recommendations
100
90
80
70
60
50
40
30
20
10
0
RR=1.12
(1.02,1.24)
RR=0.84
(0.75,0.94)
Path + Likely Path
Uncertain
Benign + Likely Benign
Among path, 88% received rec, among uncertain 74% received rec,
among benign 66% received rec
% with Any New Recommendations
78
76
RR=1.07
(0.95,1.20)
RR=1.07
(0.95,1.22)
RR=1.10
(0.96,1.26)
74
72
70
68
66
64
<2 organ systems
2 organ systems
3 organ systems
>3 organ systems
Among <2 systems 69% received rec, 2 systems 74% received rec, 3
systems 74% received rec, >3 systems 76% received rec
% with Any New Recommendations
100
90
80
70
60
50
40
30
20
10
0
RR=0.75
(0.69,0.82)
<1 yr
1-5 yrs
RR=0.66
(0.57,0.76)
6-10 yrs
RR=0.74
(0.67,0.83)
>10 yrs
Among ages <1 92% received rec, ages 1-5 69% received rec,
ages 6-10 61% received rec, ages 10+ 69% received rec
% with Any New Recommendations
100
90
80
70
60
50
40
30
20
10
0
RR=1.24
(1.12,1.38)
RR=1.20
(1.10,1.32)
Sickkids
Non SickKids
Genetics
Non Genetics
Among SK 72% received rec, non SK 89% received rec,
GEN 71% received rec, non GEN 85% received rec

~5 recommended investigations can be
anticipated to follow receipt of a CMA result

Specialist consultation, medical imaging
frequent

Multiple specialist groups implicated
 Need to be sufficient in number
 Need to be equipped to navigate result
Drivers of medical management
 Age
 <1yr most likely to receive recommendations
▪ more significantly affected, candidates for more
investigations

CMA result type
 Pathogenic results drive medical recommendations
 Uncertain results drive recommendations to a lesser
extent
▪ Suggestive of utility BUT management driven by dx results
we do not understand
▪ Potential for reclassification




Need to follow resource utilization, not just
recommendations
Need to attend to variants of uncertain
significance
Need prospective studies
Need to attend to same issues in the
context of whole genome sequencing
McLaughlin Study Team
Cheryl Shuman, Lead PI, SickKids
Ny Hoang, SickKids/Medcan
James Aw, Medcan
Riyana Babul-Hirji, SickKids
Sebastien Chernier, SickKids
Jill Davies, Medcan
Dinesh Marianayagam, Medcan
Shuye Pu, SickKids
Jim Stavropolous, SickKids
Lea Velsher, Medcan
Rosanna Weksberg, SickKids
Shoshana Wodek, SickKids
Advancing genomic medicine through research and education
% With New Recommendations
100
90
80
RR=1.1
(0.94,1.27)
70
60
50
40
30
20
10
0
Related FHx
No related FHx
% With New Recommendations
100
90
80
RR=1.1
(1.03,1.28)
70
60
50
40
30
20
10
0
Male
Female