July 18, 2013 Counsyl Tech Talk on "How I Learned to Stop Worrying about Big Data and Love the Data That Actually Counts." Speaker: Imran Haque, Director of Research, Counsyl.
Video: https://vimeo.com/71282924
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How I Learned to Stop Worrying about Big Data and Love the Data That Actually Counts - Counsyl Tech Talk
1. Counsyl
www.counsyl.com
How I Learned to Stop Worrying
about Big Data
...and love the data that actually counts
Imran S. Haque
Counsyl
18 Jul 2013
Friday, July 26, 13
2. About the Speaker
•Imran S. Haque (ihaque@counsyl.com)
•Director of Research at Counsyl
•BS EECS, UC Berkeley; PhD CS, Stanford
Friday, July 26, 13
3. About Counsyl
We have developed a single genomic test that replaces 100+ expensive assays
It has reduced the cost of carrier testing by literally one hundred fold
Bloom Syndrome $167
Canavan Disease $473
Cystic Fibrosis $506
Familial Dysautonomia $334
Fanconi Anemia $167
Gaucher Disease $467
Glycogen Storage Disease Type Ia $283
Maple Syrup Urine Disease Type 1B $557
Mucolipidosis IV $279
Niemann-Pick Disease Type A $337
Spinal Muscular Atrophy $700
Tay-Sachs Disease $473
Total $4743
Friday, July 26, 13
5. Engineering at Counsyl
How big is the data in genomics?
Wetlab
Biology
Ordering
Reporting
Billing
Fulfillment
Automation
Assay
Calling
Assay Calling
Friday, July 26, 13
9. Background
Wikipedia “Big Data”:
A collection of data sets so large and
complex that it becomes difficult to
process using on-hand database
management tools or traditional data
processing applications
Friday, July 26, 13
10. What Defines Big Data
• Computation: data so large that algorithms must be o(N1+ε):
“almost linear.”
• Handling: data so large that with tractable algorithms
communication becomes more significant than computation.
Friday, July 26, 13
11. Why Do People Care?
Big Data is fundamental to fields in which each individual piece
of data is relatively information-light, so it is necessary to
aggregate a lot of it.
Friday, July 26, 13
This particularly characterizes advertising, which funds the consumer
Internet. People are interested in Big Data as a means to an end (improving
conversion rates), not as an end in itself.
14. Short-Read Sequencing in Short
I don’t know what they want from me
It’s like the more money we come across
The more problems we see
Friday, July 26, 13
15. Short-Read Sequencing in Short
I don’t know what they want from me
It’s like the more money we come across
The more problems we see
It’s like the more
w what they wan
acro5sThe more probl
re problems we see
...
Friday, July 26, 13
16. Short-Read Sequencing in Short
I don’t know what they want from me
It’s like the more money we come across
The more problems we see
It’s like the more
w what they wan
acro5sThe more probl
re problems we see
...
Current sequencers can produce ~100Gb of short (100bp) reads/day
Friday, July 26, 13
24. Alignment Algorithms
Ning, Cox, Mullikin. Genome Res 2001
Li, Ruan, Durbin Genome Res 2008
Ferragina and Manzini, JACM 2005
Langmead et al, Genome Biol 2009
Li and Durbin et al, Bioinformatics 2009
Friday, July 26, 13
25. Alignment Algorithms
• Smith-Waterman: O(MN), large constant factor
• Hash-based Alignment: much smaller constants than SW
• MAQ, SSAHA
• Burrows-Wheeler Alignment: sublinear in size of genome
• Bowtie, BWA
Ning, Cox, Mullikin. Genome Res 2001
Li, Ruan, Durbin Genome Res 2008
Ferragina and Manzini, JACM 2005
Langmead et al, Genome Biol 2009
Li and Durbin et al, Bioinformatics 2009
Friday, July 26, 13
29. Genomics: Big Data?
Genomics appears to have all the characteristics of Big Data.
• Large quantity: ~100GB/day/sequencer
• Advanced algorithms: BWT alignment in linear/sublinear time
But characteristics of the data itself matter too!
Friday, July 26, 13
31. Clinical Genomics: Not That Big
Most of the human genome is currently non-actionable.
Whole Genome Sequencing (~3000 Mb)
Friday, July 26, 13
32. Clinical Genomics: Not That Big
Most of the human genome is currently non-actionable.
Whole Genome Sequencing (~3000 Mb)
Whole Exome Sequencing (~30 Mb)
Friday, July 26, 13
33. Clinical Genomics: Not That Big
Most of the human genome is currently non-actionable.
Whole Genome Sequencing (~3000 Mb)
Whole Exome Sequencing (~30 Mb)
Clinical Carrier Screening (~1 Mb)
Friday, July 26, 13
34. Clinical Genomics: Not That Big
Most of the human genome is currently non-actionable.
Whole Genome Sequencing (~3000 Mb)
Whole Exome Sequencing (~30 Mb)
Clinical Carrier Screening (~1 Mb)
Exome Sequencing (30 Mb)
Friday, July 26, 13
35. Clinical Genomics: Not That Big
Most of the human genome is currently non-actionable.
Whole Genome Sequencing (~3000 Mb)
Whole Exome Sequencing (~30 Mb)
Clinical Carrier Screening (~1 Mb)
Exome Sequencing (30 Mb)
Clinical Carrier Screening (~1 Mb)
Friday, July 26, 13
36. But 100Gb Is Still 100Gb, Right?
Friday, July 26, 13
37. But 100Gb Is Still 100Gb, Right?
Clinical genomics analysis is per-sample.
• Processing is embarrassingly parallel after demultiplexing.
• Handling a single sample is trivial on even a laptop.
Use ZFS and LSF/SGE, not Cassandra and Hadoop.
Friday, July 26, 13
41. Research Genomics
Counsyl runs this many samples every year; clinical = scale.
Target # Samples # SNPs
Education Level 126,559 2.2M
Breast/Ovarian Cancer 11,705 31,812
Diabetes 10,128 2.2M
Telomere Length 37,684 2.4M
Rietveld et al, Science 2013
Couch et al, PLoS Genet 2013
Zeggini et al, Nat Genet 2008
Codd et al, Nat Genet 2013
Friday, July 26, 13
42. Clinical Genomics: Big Where It Matters
Whole Genome (3000 Mb)
Clinical Genome (1 Mb)
Friday, July 26, 13
43. Clinical Genomics: Big Where It Matters
• Focusing on a small region means you can examine thousands
of people: study important regions in great depth.
• Embarrassingly parallel is a good thing: people pay the bills!
Friday, July 26, 13
44. Let’s Science Up This Data
N=83,538 samples, 493 variants
Estimated carrier frequency per population as a binomial.
Bonferroni-corrected binomial equality test comparing each population
against the pooled data finds variants that are significantly enriched/
depleted in particular populations.
Haque et al, in preparation
Friday, July 26, 13
45. Smith-Lemli-Opitz Syndrome (DHCR7)
• We see a carrier rate double the predicted literature values
(e.g., 1/57 vs 1/124 in Northwestern Europeans)
• We find previously undescribed population associations for
DHCR7:IVS8-1G>C
Population Frequency
Overall
Frequency
P-value N
AJ 1 in 46 1 in 96 1.18E-11 4330
➡EA 0 1 in 96 1.56E-07 2739
Haque et al, in preparation
Friday, July 26, 13
46. Genetic Disease in South Asians
Cystic Fibrosis (CFTR)
• 1/57 observed vs 1/118 in literature.
GJB2-related DFNB1 nonsyndromic hearing loss and deafness
• Literature claims 1/133 with 35delG, but we find 1/2191.
• 36/2191 carriers, 35 for W24X.
Progressive cone dystrophy/achromatopsia (CNGB3)
• R403Q present in 1/18: 30% of carriers in 4% of tested pop.
Haque et al, in preparation
Friday, July 26, 13
47. Size Doesn’t Matter, It’s How You Use It
• Genomics has a real ground truth.
• Genomics has a real impact.
Clinical genomics is interesting independently of “Big”ness.
Friday, July 26, 13
48. Future of Genomics
Cratering prices drive technological shifts.
Technologies at the research frontier will become commercialized.
• Whole-genome association studies
• RNA-seq and transcriptomics
• Epigenomics
• Pathogen sequencing and metagenomics
Friday, July 26, 13
49. Where Are We Now?
• Theory has been developed in academia and government.
• Scale-up is just beginning in industry: started with tool
vendors, now reaching applications companies.
• New scales of data will feed back into basic R&D.
Friday, July 26, 13
50. Recap
Big Data =
•“near linear” algorithms
• communication is
harder than computation
Short-read sequencing
produces large amounts
of data.
Useful clinical insights
are mostly derived from
embarrassingly-parallel
small data.
“Small data” genomics is
highly impactful in its
own right.
Genomics may enter a
“big data” phase in the
future with new
methods.
Friday, July 26, 13