Joaquín Dopazo, Área de Bioinformática,Fundación Progreso y Salud,Nodo de Genómica Funcional, (INB-ELIXIR-es), Bioinformática de ER (BiER-CIBERER), CDCA, Hospital Virgen del Rocío, Sevilla

1. Big Data Genómico
Mesa redonda: Desde el Big Data a la medicina de precisión
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ENCUENTRO «ERNEST LLUCH»
Big Data y Real World Data en el análisis de la utilización, seguridad y
efectividad de medicamentos, tecnologías e intervenciones sanitarias
CUIMPB Barcelona, 9 de junio, 2019
Joaquín Dopazo
Área de Bioinformática,
Fundación Progreso y Salud,
Nodo de Genómica Funcional, (INB-ELIXIR-es),
Bioinformática de ER (BiER-CIBERER),
CDCA, Hospital Virgen del Rocío, Sevilla
http://www.clinbioinfosspa.es
http://www. babelomics.org
@xdopazo, @ClinicalBioinfo

2. The clinical bioinformatics area
http://www.clinbioinfosspa.es/
The Bioinformatics Area, created in June 2016 in the Fundación Progreso y Salud, has as main goal supporting
the Program of Personalized Medicine of the Andalusian Community by facilitating the use of genomic data for
precision diagnosis and treatment recommendation, implementing opportunities for the prospective innovation
in health care in the public health system .
Data analysis ...and… exploitation
12Million,
since 2001
Mission: facilitating the use of genomic big data in the clinic

3. The two tiers of personalized medicine:
Use and re‐use of genomic data to
generate new knowledge
First tier: use of patient genomic data
for precision diagnosis (typically RDs)
and treatment recommendation
(cancer).
Extensively implemented in hospitals
Requires information on gene to
phenotype association
Second tier: use clinical data (eHR) along with
genomic data for preventive medicine, biomarker
discovery and clinical research.
Andalusian Population Health Database, with over
12M people since 2001.
Aim: converting the whole Public Health System
(SAS) into a huge prospective clinical study (GDPR
compliance within SAS)

4. Use of genomic data in the public health
system requires sustainability
• Use: Increasingly DSS, and decreasingly research
• DSS
• User: DSS geneticist, research bioinformatician
• Routine genomic analysis (diagnosis, treatment recommendation) with
tools for end users, which involves hiding the complexity of the analysis.
• A solution for the management of genomic data must be integrated the
same way other analyses of the health system are.
• GDPR compliance and data
reusability:
Genomic data must be stored
within the health system, linked
to clinical data the same way
other data are for further
potential prospective clinical
studies

5. Second tier: exploitation of the clinical Big Data
The population health database
Possibly the largest database ever created with detailed clinical
data, storing information on 12.083.681 patients since 2001
Genomic data
collected by the
SAS is being
uploaded onto
BPS, and soon
Digital pathology
and Liquid Biopsy
will be as well.
More complex
queries, including
the genetic basis
of the traits, will
be possible
∑
Genomic
biomarkers
PADIGA
Liquid
biopsy

6. Why doctors wash hands?
Small‐scale big data analysis in 1840
Ignaz Philipp
Semmelweis
(1818‐1865)
Observation: doctors' wards had three times the
mortality of midwives' wards (30% vs <5%).
Washing hands reduced the mortality <1%
Health records, beyond to keep track of the
histories of patients, can collectively tell
histories on the diseases, the processes, etc.
Semmelweis, by
looking at the HRs,
made an interesting
observation: giving
birth assisted by a
doctor was dangerous

7. However, clinical data exploration and
research can give new information different
from the original storage purpose
Clinical big data exploitation requires a
digital transformation of health systems
Data digitalization is necessary but not
sufficient for big data exploitation.
Digitalization has been mainly designed
to control processes and to facilitate the
access to patient’s data.

8. 1E‐08
0,0000001
0,000001
0,00001
0,0001
0,001
0,01
0,1
1
10
100
1000
10000
100000
1000000
2001‐01‐01
2002‐01‐01
2003‐01‐01
2004‐01‐01
2004‐12‐31
2005‐12‐31
2006‐12‐31
2007‐12‐31
2008‐12‐30
2009‐12‐30
2010‐12‐30
2011‐12‐30
2012‐12‐29
2013‐12‐29
2014‐12‐29
2015‐12‐29
2016‐12‐28
2017‐12‐28
2018‐12‐28
2019‐12‐28
2020‐12‐27
2021‐12‐27
2022‐12‐27
2023‐12‐27
2024‐12‐26
2025‐12‐26
2026‐12‐26
2027‐12‐26
2028‐12‐25
2029‐12‐25
Thousands of dollars
Cost of human genome sequencing
The future of data generation
1$ genome?
• DNA sequencing prices
will soon be
comparable to any
other conventional
test.
• Actually, they already
are (if the whole
treatment is
considered)
Health systems will
become the main
genomic data
generator in a near
future
Radiography
TAC
TAC‐PET

9. The future of data generation
PanelPanel WESWES WGSWGS
Obstacles: Lack of interpretability on most of the findings
WES yields 50 – 80K variants
WGS yields 1‐2 M variants
Many variants of unknown significance (VUS)

10. The future of generation of information:
Diagnostic (RD) ore treatment (cancer) biomarkers
About 6000 rare disease over
80% with genetic cause
In less than 5 years most of the
rare variation will be known
About 6000 rare disease over
80% with genetic cause
In less than 5 years most of the
rare variation will be known
Today 1‐3 new therapies enter in hospitals
every Q
In less than 5 years WES and WGS will
increase therapeutic options for patients
Today 1‐3 new therapies enter in hospitals
every Q
In less than 5 years WES and WGS will
increase therapeutic options for patients
RD & cancer are
genetic diseases
with strong
penetrance

11. AI can help with the generation of information for
the interpretation of the findings
Making use of the information currently
available on pathologic variation, the
potential pathologic character of a new
mutation can be predicted (to some extent)
with AI methods, that clearly outperform
conventional statistic methods

12. • Modular nature of genetic diseases: Causative genes
for the same or phenotypically similar diseases may
generally reside in the same biological module.
• Mechanistic models use pathways as maps of protein
functional interplay to convert gene measurements
into cell functional activity profiles.
• Mechanistic models predict the effect that
interventions over the pathway components have
over the pathway functional activity.
• However, the generation of biological knowledge (e.g.
pathways) is a slow and artisanal procedure carried
out by individual laboratories and requiring a lot of
validation.
Generation of Biological knowledge:

13. The last frontier:
Knowledge generation from data using AI
Topol, 2019, Nat. Med.
Variables
Samples
Variables
Samples
Curse of dimensionality
Learning biological knowledge from
the data is currently quite complex.
New methods for feature selection,
dimensionality reduction, multi‐
view learning and network learning
need to be developed.
Optimal ML
scenario

14. Transition to models that integrate omic
and clinical data
…
…
Genomic Clinic
Clinical study
• Treatment of genomic data
for research purposes (GDPR)
• Principle of use of minimal
personal data
• Data pseudoanonimization
• Each study requires of a
specific genomic and clinical
data collection into an
external database
• Serious security concerns
(genomic + clinical data
outside the hospital)
• Static clinical data (e.g. if a
control becomes a case the
external DB will not be
updated)
• Limited genomic data reuse
for purposes different from
the original study.
…
…
Genome Clinic
…
.
Study1 ….. Studyn
Query engine
• Clinical data dynamically
associated to genomic data
• Possibility of many clinical
studies by reanalyzing
genomic data under diverse
perspectives (with no extra
investment)
• Growing genomic DB with
increasing study possibilities
• The whole health system
becomes a enormous
potential prospective clinical
study
Today’s information generation Possibilities in systems with universal eHR
Possibly the largest database
ever created with detailed
clinical data, storing information
on 12.083.681 patients since
2001
GDPR
(minimal data use)

15. Possible future models for large‐scale
data sharing
…
Study1
Low risk.
Aggregated data
Genomic Clinic
…
Risk
…
.Study1 ….. Studyn
Federated External repository
Nordic countries
MEGA 1Million genomes
Genomics England Ltd
CIBERER

16. ...the INB-ELIXIR-ES, National Institute of Bioinformatics
and the BiER (CIBERER Network of Centers for Research in Rare Diseases)
@xdopazo
@ClinicalBioinfo
Follow us on
twitter
https://www.slideshare.net/xdopazo/
Clinical Bioinformatics Area
Fundación Progreso y Salud, Sevilla, Spain, and…

17. ?
eHR
K
NO
YES
D
I: patient`s Información
G: patient`s Genome
D: high precision Diagnosis
Knowledge
K
Clinical research
D
Knowledge
Diagnosis / Diagnosis /
therapy
G
I
Sequencing
Unit
11
22
33
44
55
66
77
88
Genomic data in the clinic:
Transition from research and discovery to DSS
?
Bioinfo Unit
Corporative
Genetics Unit