May 11, 2016
Open competitions bring new minds, skills and collaborations to problems in biomedical research.
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Bratislava Milenkovic
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Hours before the close of Kaggle's competition to find out why
almost one-third of women in the United States are not screened for cervical
cancer, the leading team has submitted the 115th iteration of its model. Forty
groups around the world are competing to win US$100,000 in a challenge sponsored by biotechnology company
Genentech.
The models are based
on analyses of a 150 gigabyte database of de-identified patient data, says
computational biologist Wendy Kan, who set up the challenge and works at Kaggle
in San Francisco, California, a company that runs predictive modelling and
analytics competitions that allow data scientists to compete to solve complex
problems. In addition to finding solutions, contestants are asked to explain
their reasoning. “It's very important for us to tell a story,” Kan says. Later,
on a Kaggle forum, a member of the winning team presents two of the group's
hypotheses: multiple chronic diseases and mental-health issues are major
factors in why some women skip screening.
Another Kaggle
challenge, which began in December, asked participants to transform the
diagnosis of heart disease by coming up with an algorithm to examine cardiac
magnetic resonance imaging (MRI) scans to see how well the heart is pumping
blood — “A very difficult problem,” Kan says. Entrants used a cardiac MRI data
set provided by the US National Heart, Lung and Blood Institute, and 192 teams
were in the running for the $200,000 prize when the competition closed. The victors were two
quantitative analysts who have worked with hedge funds, but had no experience
in cardiology.
So far, more than
450,000 data scientists have tried their hand at Kaggle's predictive-modelling
puzzles, says economist Anthony Goldbloom, founder and chief executive of the
organization. The problems — many pertaining to health, but others in fields
that range from criminology to search technology — are set up so that the
background of entrants doesn't matter, he says. As long as they have suitable
modelling skills, no particular experience or qualifications are needed.
“They are all smart,
highly motivated and incredibly capable,” adds Goldbloom. “The winning margin
is usually very small; often the difference between first and second isn't even
statistically significant.”
Kaggle is one of a
number of organizations running open global challenges in life sciences to
address knotty problems in basic biology, clinical research or health care. The
approach is steadily gaining backers in academic laboratories and classrooms,
drug companies and government agencies as a way to bring well-defined, but
thorny problems to the attention of brilliant minds around the world.
The design of the
competitions varies from challenge to challenge and host to host. Some ask for
modelling algorithms, others for ideas, and still more for prototype medical
solutions. Prizes are often offered, although participants usually insist that
money is not the main motivation. Some of the winning solutions, especially
those sponsored by industry, remain secret, but others are made openly
available and a few have already resulted in advances in clinical research.
Clockwork origins
Competitions in
science and engineering have a long history. In 1714, the Longitude Act saw the
UK government offer a reward of £20,000 (well over £2,000,000 ($2,865,400) in today's
money) for a solution to the problem of calculating longitude at sea. Not just
one, but two answers emerged: the marine chronometer, developed by clockmaker
John Harrison, which kept time at sea well enough for navigators to calculate
longitude effectively; and a method for devising longitude from the motion of
the Moon borne of a combined effort by scientists, including mathematician John
Hadley and astronomer Tobias Mayer.
But it took the
advent of the Internet for crowdsourced medical contests to really take off,
notably with the Critical Assessment of Protein Structure Prediction (CASP)
experiments, which have seen research groups test their methods for predicting
3D protein structures against those of their peers since 1994.
The competitions
gained more industry backing as pharmaceutical companies began to struggle with
their pipelines. The crowdsourcing firm InnoCentive, for example, formed in
2001, a time when “the pharmaceutical industry needed to rethink its business
model”, recalls Alph Bingham, co-founder of the company based in Waltham,
Massachusetts, and then a vice president at pharmaceutical giant Eli Lilly.
“The Internet let you access minds on a scale and a scope that had never been
possible before.”
Spun out from Eli Lilly, InnoCentive has held more than 2,000 open
challenges and attracted more than 375,000 'solvers'. The continual string of
challenges can be tightly focused and relatively small, such as a $30,000 challenge to
find a minimally invasive skin-biopsy method to measure gene expression, or
attempt to tackle larger problems, such as a major $500,000 challenge
sponsored by the US National Institutes of Health (NIH) to look for robust
methods to examine individual cells. Proposals such as these are inherently
risky
Scientists from
around the world competed to win a BioMed X fellowship in Heidelberg, Germany.
Indeed, challenges
seem to hold a number of advantages over conventional research practices. One
of the leading crowdsourcing initiatives is the Dialogue for Reverse
Engineering Assessments and Methods (DREAM) Challenges programme, which sees
groups compete in open competitions to solve complex modelling problems in
systems biology, says Gustavo Stolovitzky, co-founder of the project and
computational biologist at IBM's Thomas J. Watson Research Center in Yorktown
Heights, New York.
When dozens of teams
around the world take on a DREAM project, they often accomplish in months what
would take a single research group years, “since you can multiply the number of
people working on the problem by 50 or 100,” says Stolovitzky. Many challenges
also bring in researchers from other fields, who may approach problems in ways
that those closely acquainted with them would not.
Just as crucially,
challenges jump-start collaborative communities. For instance, the ICGC-TCGA
DREAM Somatic Mutation Calling Meta-pipeline Challenge is a collaboration
between DREAM, the International Cancer Genome Consortium, The Cancer Genome
Atlas and biomedical research organization Sage Bionetworks in Seattle,
Washington. Its aim is to improve standard methods for identifying
cancer-associated mutations and rearrangements in whole-genome sequencing. In
the process, they are building an ongoing community in which researchers can
find the best and latest algorithms, rather than having to go to scientific
journals.
Crowdsourced
tournaments can also open up access to data — either those aggregated
specifically for the purpose, such as Kaggle's cervical-cancer and cardiac MRI
databases, or data sets that would otherwise lie dormant. “There are too many
data silos in which researchers hoard their data, sometimes for years,”
Stolovitzky says. “Ultimately, everybody should be able to look at that data
with information about how the data was gathered, allowing collaboration and
data sharing in a positive and meaningful way.”
In addition, contests
can lower the legal barriers that plague collaborations between institutions or
companies, says Bingham. “They offer ways to engage all these different people
without having to precede that whole process with 200 days of legal briefs
being exchanged between institutions,” he says.
For these contests to
achieve these positive impacts, however, they have to be well managed.
Crowdsourcing is of little help in areas in which research is at such an early
stage that the organizers can't ask the right questions. For any challenge to
work, the problem must be well-defined and able to be judged fairly, says
systems biologist Stephen Friend, co-founder and director of Sage Bionetworks.
It's also important for an impartial expert in the field to act as a convener
and nurture the emerging community, he says.
Non-profit
foundations — increasingly important providers of research funding — are also
making use of crowdsourcing. Often these focus on diseases that drug companies
rarely target (see page S68).
One example is Prize4Life in Berkeley, California, founded in 2006 when Harvard
business school graduate Avichai Kremer was diagnosed with amyotrophic lateral
sclerosis (ALS; also know as motor neuron disease), and best known for its $1-million contests
Participants at a
Massachusetts Institute of Technology Grand Hack discuss health-care
challenges.
“Prizes can really
bring a new population of researchers into the field,” says neuroscientist Neta
Zach, chief scientific officer at Prize4life. “And a lot of them continue to
work on ALS.” Prize4Life's first major challenge addressed the lack of useful
biomarkers for ALS progression. “We expected that the tool would be based on
measurements from blood or cerebral spinal fluid,” Zach says. Instead, the
winning tool in 2011 was a more creative solution: a pain-free non-invasive
medical device that measures the flow of electrical current through muscle
tissue. The winnings helped to build the San Francisco start-up Skulpt, which
is testing such devices in ALS trials (as well as offering them to consumers as
fitness tools).
The foundation also
partnered with DREAM and InnoCentive in a $50,000 challenge to predict the progression of ALS. When the
predictions of the winning algorithm were compared with those made by ALS
clinicians in the assessment of 14 people with ALS (R. Kuffner et al. Nature
Biotechnol. 33, 51–57; 2015), “the algorithm outperformed
each and every one of the clinicians on each and every one of the patients”,
Zach says. The model is now used to make ALS clinical trials more efficient and
their results clearer — a better understanding of ALS makes it easier to assess
the benefits of treatment.
“Prizes can really
bring a new population of researchers into the field.”
DREAM was launched in
2006 by Stolovitzky and systems biologist Andrea Califano at Columbia University
in New York City to improve the state of the art in systems-biology modelling.
As well as solving problems, DREAM challenges validate the solutions.
Sometimes when
data-science groups tackle a difficult problem, they can convince themselves
that they have produced a good solution, rather than actually solving it well.
Stolovitzky calls this the “self-assessment trap”, which can lead to mistakes
such as overfitting models to one set of data. But if 50 DREAM teams are
involved, “we can see if we can really find a clear signal in the data”, he
says.
In 2012, DREAM joined
forces with Sage Bionetworks, which had created Synapse, a pioneering
open-computing platform for data analysis and sharing. The first joint
challenge generated models to classify the aggressiveness of breast cancer. The
models clearly performed better than today's commercial tests, says Friend.
“More importantly, the challenge showed that people who had not generated the
data were able to get deep insights,” he says. “And the electrical engineer who
won had very little chemical background.”
Rising to the
challenge
Competitions are
beginning to exploit the opportunities provided by data contributed directly by
patients. Sage, for example, created mPower, an app that uses iPhone sensors to
measure symptoms of Parkinson's disease progression such as dexterity or gait.
And Sage has partnered with other groups, such as Oregon Health and Science
University in Portland and Harvard University in Cambridge, Massachusetts, to
create numerous such apps, which can very quickly provide high-quality data.
“We have over 200,000 people who have said, I want to share my data with
qualified users,” Friend says.
In November 2015, a
DREAM hackathon drew participants for two evenings of pizza, beer and the
opportunity to begin interpreting data from tens of thousands of mPower users.
That event reflects another trend in crowdsourcing — the rapid spread of
biomedical hackathons. These are designed to bring experts from different
disciplines face to face. The Hacking Medicine initiative at the Massachusetts
Institute of Technology (MIT) in Cambridge, for instance, has so far hosted
almost 50 such events, teaming up engineers and data scientists with clinicians
in 1- or 2-day events that are meant to quickly and iteratively work towards
initial solutions to a host of health-care problems.
Among early results
is an infant-resuscitation device for use in developing countries. The Ugandan
paediatrician who first presented the problem has now taken the device into
clinical trials in his country. The MIT initiative has helped to spark similar
gatherings in places such as India and Uganda, led by the Consortium for
Affordable Medical Technologies at Massachusetts General Hospital in Boston.
Bringing researchers
with varied expertise and skills together in one physical location can
accelerate research. The BioMed X Innovation Center in Heidelberg, Germany, has
gone further with what co-director, and biologist, Christian Tidona describes
as an “outcubator”. Researchers compete not to come up with the best solution,
but for the chance to try.
BioMed X begins by
posting a very specific problem from one of its sponsors online. This could be
exploring a new drug target or an area of treatment new to the sponsor. These
requests typically get 400–600 responses from around the world. BioMed X picks
15 of the most promising concepts submitted and brings their creators to
Heidelberg, where they form teams for an intense 5-day competition. The winning
group then tackles the problem in two- to four-year fellowships in Heidelberg.
One of the first
teams to go through the four-year exercise — made up of researchers from
Germany, Slovenia and Egypt — created bioinformatics tools for designing highly
selective inhibitors of kinases, proteins that play a part in many diseases.
The sponsor, Merck, bought the intellectual-property rights and then licensed
them back to the team, which formed a start-up company to develop the
technology.
Rules for the fight
The benefits for
research are clear, but what is it that drives participation in crowdsourced
competitions? When a challenge is centred in a researcher's field, typically
the greatest incentives to participate are the chance to publish a paper in a
top journal and to network with peers, organizers say.
“At the end of the
day, cash is often a scorecard, not a paycheck.”
But often the
entrants are not the usual suspects. “They're also gadgeteers, basement
inventors and weekend engineers,” says Bingham. “It's not a bunch of
French-literature majors that are solving our chemistry problems, but it might
be physicists or intellectual-property attorneys or biologists.” Even in
competitions with cash prizes, “at the end of the day, cash is often a
scorecard, not a paycheck”, he says. Challenges would be “a silly way to make
money”, says Goldbloom. The main draw for participants is what originally led
him to found Kaggle — the desire for “access to interesting data sets and
interesting problems”.
For medical firms, the challenges often
provide a relatively quick and inexpensive way to solve tricky problems,
Bingham says. At the same time, he points out, “in order to bring a product to
market, they usually have to solve a thousand problems of equal complexity”.
For all concerned, “the wisdom of crowds works beautifully in a great
percentage of the cases”, says Stolovitzky. “We're seeing a lot more buy-in for
these challenges. If you can multiply the number of people, you can accelerate
the research.”
http://www.nature.com/nature/journal/v533/n7602_supp/full/533S62a.html
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