Channel-Independent Viterbi Algorithm (CIVA) for DNA

SequencingXiaohua (Edward) Li

Department of Electrical and Computer Engineering

State University of New York at Binghamton

Outline

• Introduction• CIVA• Use CIVA for base-calling• Simulations• Conclusions

Introduction: DNA sequencing

• DNA sequencing (base-calling)• Procedure

– template, PCR, electrophoresis, gel image, trace file– Base-caller

Introduction: Base-caller

• Base-calling: detect DNA base sequence• Approaches

– Manual reading, automated by heuristic knowledge– Image processing with signal models (ABI, Phred)– Deconvolution with communication (ISI) signal

model, e.g., MLSE, MAP

Proposed Method: CIVA

• Our method: with ISI model, robust to signal irregularity• Difficulty comes from irregular trace signal

– Amplitude and position jitter– Short signal, limited samples, yet time-varying

• Solution: CIVA– joint symbol/position optimization

– without channel estimation

CIVA: Basic Idea

)(

0

0

n

ss

ss

hh

hh

xx

xx

LMPnLMn

Pnn

L

L

MPnMn

Pnn

V

• List all possible symbol matrices S(n), • Find a probe for each possible S(n)

• Use all probes to determine S(n) from X(n)

)()( nn SX H :case Noiseless

ijnn ijii ,)(;)( 0gS0gS

CIVA: Properties

• CIVA: a trellis searching algorithm where metrics are calculated by probes

• Properties– Near optimal for even ill-conditioned channels– No channel estimation, channel independent– High computational complexity

• Applications– Direct application: system with simple signaling and

short channel, e.g., GSM, sensor networks, base-calling

– Future: more application with complexity reduction

CIVA for Base-calling

• Model trace signal with communication system

• Channel effect introduces ISI)()()( nnn VBX H

Symbol Matrix Structure

}

1

0

0

0

,

0

1

0

0

,

0

0

1

0

,

0

0

0

1

,

0

0

0

0

{.

)()()(

n

Tn

Gn

An

Cn

n

LMPnLMn

Pnn

b

b

b

b

Pnnn

bb

bb

bb

bbB

:values 5 has symbol Each

:Matrix Symbol

Probe Construction

ji

jif ji

ki

i

ii

if

if

:conditions metric satisfy Probes

vectors testing several contains usually Probe

probe a find matrix symbol eachFor

,0

,0),(

},,{

.,

1

GB

ggG

G

GB

Probe Construction Example

},,**,{*},,*,*,{*

},*,*,{*},,,,{

)0

.1

1,

1

0,

0

1,

1

1

]}11[],01[],10[],00[{

3210332102

3210132100

3210

ggggGggggG

ggggGggggG

gB

gggg

B

testing) nonzero denotes (* probes Construct

(

matrix symbol eachfor vectors testing Find

marices symbolfour have we Assume

ii

i

Trellis Metric Calculation

||||

:Example

if

if e wher

probe everyfor

metrics calculate matrix sample received eachFor

13,2,01

3

00

1

1

)()(

]),([

||)(||]),([

,)(

,)(]),([

]),([]),([

),(

gXgX

GX

gXGX

0gBgX

0gBgXgX

gXGX

G

X

Gg

nn

nf

nnf

n

nnf

nfnf

n

mm

m m

mim

mim

m

mi

i

im

CIVA Trellis Search

]),([)1({min)(

)](),([minarg )}({

liij

nn

nfnn

nnf

GX

GXG

:search trellis by

procedure this realizeCIVA

sequence probe by

determined is sequence Symbol

:matrices probe optimal

the find matrices, sample

received of sequence aFor

Special Consideration for DNA Trace Signal

• Amplitude jitter– solved inherently

• Limited trace samples and time varying – fast convergence of CIVA

• Timing jitter – looking for best timing for each

sample

Simulations: Experiment 1

• A trace file with reference bases from Staden Package• Normalize trace, find approximate base interval, apply

CIVA with M=P=1 (2-tap channel. 25 trellis states, 125 transitional paths)

• Results: less than 3% error compared with reference

Simulations: Experiment 1• Two zoom-in sections

– #1. with confident base detections

– #2. with undetermined N

Simulations: Experiment 2

• A gel image from Prof. S. Gal with low quality

• Scanning to trace signal

Simulations: Experiment 2

• Apply CIVA for base-calling

• A zoom-in section

Conclusions

• CIVA algorithm proposed for DNA sequence base-calling

• Robust to signal irregularity with affordable computational complexity

• Experiments show positive performance• More experiments are required for evaluation