Applying Hidden Markov Models to
Bioinformatics
Conor Buckley
Outline
What are Hidden Markov Models?
Why are they a good tool for Bioinformatics?
Applications in Bioinformatics
History of Hidden Markov Models
HMM were first described in a series of statistical
papers by Leonard E. Baum and other authors in the
second half of the 1960s. One of the first applications
of HMMs was speech recogniation, starting in the
mid-1970s. They are commonly used in speech
recognition systems to help to determine the words
represented by the sound wave forms captured
In the second half of the 1980s, HMMs began to be
applied to the analysis of biological sequences, in
particular DNA.
Since then, they have become ubiquitous in
Source: http://en.wikipedia.org/wiki/Hidden_Markov_model#History
What are Hidden Markov Models?
HMM: A formal foundation for making probabilistic
models of linear sequence 'labeling' problems.
They provide a conceptual toolkit for building
complex models just by drawing an intuitive picture.
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
What are Hidden Markov Models?
Machine learning approach in bioinformatics
Machine learning algorithms are presented with
training data, which are used to derive important
insights about the (often hidden) parameters.
Once an algorithm has been trained, it can apply these
insights to the analysis of a test sample
As the amount of training data increases, the accuracy
of the machine learning algorithm typically increasess
as well.
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
Hidden Markov Models
Has N states, called S1, S2, ... Sn
There are discrete timesteps, t=0, t=1
N=3
t=0 S2
S1
S3
Source:
http://www.autonlab.org/tutorials/hmm.html
Hidden Markov Models
Has N states, called S1, S2, ... Sn
There are discrete timesteps, t=0, t=1
For each timestep, the system is in exactly one
of the available states.
N=3
t=0 S2
S1
S3
Hidden Markov Models
S1 S2 S3
Bayesian network with time slices
Bayesian Network Image:
http://en.wikipedia.org/wiki/File:Hmm_temporal_bayesian_net.svg
A Markov Chain
Bayes' Theory
• (statistics) a theorem describing how the conditional probability of a set
of possible causes for a given observed event can be computed from
knowledge of the probability of each cause and the conditional
probability of the outcome of each cause
- http://wordnetweb.princeton.edu/perl/webwn?s=bayes%27%20theorem
Building a Markov Chain
Concrete Example
Two friends, Alice and Bob, who live far apart from each other and who talk
together daily over the telephone about what they did that day.
Bob is only interested in three activities: walking in the park, shopping, and cleaning
his apartment.
The choice of what to do is determined exclusively by the weather on a given day.
Alice has no definite information about the weather where Bob lives, but she knows
general trends.
Based on what Bob tells her he did each day, Alice tries to guess what the weather
must have been like.
Alice believes that the weather operates as a discrete Markov chain. There are two
states, "Rainy" and "Sunny", but she cannot observe them directly, that is, they are
hidden from her.
On each day, there is a certain chance that Bob will perform one of the following
activities, depending on the weather: "walk", "shop", or "clean". Since Bob tells
Alice about his activities, those are the observations.
Source: Wikipedia.org
Hidden Markov Models
Building a Markov Chain
What now?
* Find out the most probable output sequence
Vertibi's algorithm
Dynamic programming algorithm for finding the most
likely sequence of hidden states – called the Vertibi path
– that results in a sequence of observed events.
http://pcarvalho.com/forward_viterbi/
Vertibi Results
Bioinformatics Example
Assume we are given a DNA sequence that begins in
an exon, contains one 5' splice site and ends in an
intron
Identify where the switch from exon to intron occurs
Where is the splice site??
Sourece: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
Bioinformatics Example
In order for us to guess, the sequences of exons, splice
sites and introns must have different statistical
properties.
Let's say...
Exons have a uniform base composition on average
A/C/T/G: 25% for each base
Introns are A/T rich
A/T: 40% for each
C/G: 10% for each
5' Splice site consensus nucleotide is almost always a
G...
G: 95%
A: 5%
Sourece: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
Bioinformatics Example
We can build an Hidden Markov Model
We have three states
"E" for Exon
"5" for 5' SS
"I" for Intron
Each State has its own emission probabilities which
model the base composition of exons, introns and
consensus G at the 5'SS
Each state also has transition probabilities (arrows)
Sourece: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
HMM: A Bioinformatics Visual
We can use HMMs to generate a sequence
When we visit a state, we emit a nucleotide bases on the emission
probability distribution
We also choose a state to visit next according to the state's
transition probability distribution.
We generate two strings of information
Observed Sequence
Underlying State Path
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
HMM: A Bioinformatics Visual
The state path is a Markov Chain
Since we're only given the observed sequence, this underlying
state path is a hidden Markov Chain
Therefore...
We can apply Bayesian Probability
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
HMM: A Bioinformatics Visual
S – Observed sequence
π – State Path
Θ – Parameters
The probability P(S, π|HMM, Θ) is the product of all emission
probabilites and transition probilities.
Lets look at an example...
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
HMM: A Bioinformatics Visual
There are 27 transitions and 26 emissions.
Multiply all 53 probabilities together (and take the log, since these are
small numbers) and you'll calculate log P(S, π|HMM, Θ) = -41.22
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
HMM: A Bioinformatics Visual
The model parameters and overall sequences scores are all
probabilities
Therefore we can use Bayesian probability theory to manipulate these
numbers in standard, powerful ways, including optimizing parameters and
interpreting the signifigance of scores.
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
HMM: A Bioinformatics Visual
Posterior Decoding:
An alternative state path where the SS falls on the 6 th G instead of the 5th (log
probabilities of -41.71 versus -41.22)
How confident are we that the fifth G is the right choice?
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
HMM: A Bioinformatics Visual
We can calculate our confidence directly.
The probability that nucleotide i was emitted by state k is the sum of the probabilities of
all the states paths use state k to generate i, normalized by the sum over all possible state
paths
Result: We get a probability of 46% that the best-scoring fifth G is correct and 28% that the
sixth G position is correct.
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
Further Possibilites
The toy-model provided by the article is a simple
example
But we can go further, we could add a more realistic
consensus GTRAGT at the 5' splice site
We could put a row of six HMM states in place of '5'
state to model a six-base ungapped consensus motif
Possibilities are not limited
The catch
HMM don't deal well with correlations between
nucleotides
Because they assume that each emitted nucleotide
depends only on one underlying state.
Example of bad use for HMM:
Conserved RNA base pairs which induce long-range
pairwise correlations; one position might be any
nucleotide but the base-paired partner must be
complementary.
An HMM state path has no way of 'remembering' what a
distant state generated.
Source: http://www.nature.com/nbt/journal/v22/n10/full/nbt1004-1315.html#B1
Credits
http://
www.nature.com/nbt/journal/v22/n10/full/nbt1004-131
5.html#B1
http://en.wikipedia.org/wiki/Viterbi_algorithm
http://en.wikipedia.org/wiki/Hidden_Markov_model
http://en.wikipedia.org/wiki/Bayesian_network
http://www.daimi.au.dk/~bromille/PHM/Storm.pdf
Questions?
