Overview of how we at Ingenuity interpreted the exomes of a family in which only some person/people -- we had to guess whom -- store too little high-density lipoprotein. Organized by CAGI (genomeinterpretation.org) as one of their yearly challenges, the low-HDL study drew 39 entrants; we were pleased to score best, and to thus be invited to explain how we interpreted the data, and what we found.

1.
Genomic
21…
Spo3ng
a
proband
with
Ingenuity
Variant
Analysis
Nathan
Pearson
Principal
Genome
Scien0st
Ingenuity
Systems/QIAGEN
npearson@ingenuity.com
Tweet
@genomenathan,
@ing_sys
Created for CAGI 2013 Pearsongenomeinterpretation.org

2. 2
Danke
schön!
Proprietary and Confidential
• Sequencees
• Data
providers
&
assessors
• CAGI
organizers
• Sohela
Shah,
Dan
Richards,
Doug
BasseO
Created for CAGI 2013 Pearsongenomeinterpretation.org

3. 3
How
we
did
Proprietary and Confidential
0
10
20
30
40
50
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
predicted
P(has
low
HDL)
HDL
(hidden)
Created for CAGI 2013 Pearsongenomeinterpretation.org

4. 4
How
we
did
it
Proprietary and Confidential
• Use
Ingenuity
Variant
Analysis
• Compare
low-­‐HDL
quartet
(cases)
to
Crohn
exomes
(controls)
• Find
rare,
func0onally
suspect
variants
in
quartet
• Among
those,
count
singletons/person
• Invoke
prior
P(
|
,
1
sick,
$
>>
0)
~
1
Created for CAGI 2013 Pearsongenomeinterpretation.org

5. 5
• Secure
web
pla_orm
for
interpre'ng
called
human
genomes
• Smart
interface
to
flexibly
annotate
&
compare
genomes,
in
order
to
shortlist
candidate
variants,
genes,
&
gene
sets
• Leverages
func;onal
knowledge
base,
with
rigorous
cura0on
of
published
findings,
well
structured
ontology,
smart
interac0on
modeling
• Sta;s;cally
robust
methods
for
interpre0ng
(mul0-­‐)proband,
matched
tumor,
(mul0-­‐)kindred,
&
big
case/control
cohort
studies
• Lets
users
readily
share
samples
(pool
cases,
trade
controls)
&
analyses
Proprietary and Confidential
Ingenuity®
Variant
Analysis™
in
a
nutshell
Created for CAGI 2013 Pearsongenomeinterpretation.org

6. 6Proprietary and Confidential
Live
walkthrough
with
case/control
exome
data
Created for CAGI 2013 Pearsongenomeinterpretation.org

7. 7
• Top
candidate
variant
[censored]?
• N
low,
methods
young…so
need
skill
(Variant
Analysis),
priors
(behavior),
luck
• Func0onal
annota0on,
sensible
filtering,
&
extra
controls
help
• All
here
welcome
to
try
out
Variant
Analysis
–
see
me.
• Ques0ons?
Proprietary and Confidential
Take-­‐home
Created for CAGI 2013 Pearsongenomeinterpretation.org