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Table 1 Description of unrelated haplotyping programs, divided into four classes based on method.

From: A comprehensive literature review of haplotyping software and methods for use with unrelated individuals

Program name Algorithm Outputa Missing datab Assumptionsc Key features Limitations MAX subjects, loci and type Platform Ref.d
Parsimony methods          
1. Simple parsimony          
HAPAR Parsimony HA No None Overcomes limitations of HAPINFREX May be susceptible to HWE departures Practical limit, biallelic PC/UNIX [39]
      Increasing sample size improves
accuracy 		    
HAPINFERX Clark's HA No None Intuitive method, fast May fail to start Practical limit,
biallelic/multiallelic 		UNIX [37]
      Reduced number
of haplotypes 		Sensitive to
data order 		   
      No limit on
number of loci 		Unstable and
erroneous
estimates 		   
2. Phylogeny          
BPPH IP HA No IP Similar to HAPH User interface Practical limit, biallelic MAC [45]
      Speed     
DPPH PP HA No PP Handles large datasets Theoretical Practical limit, biallelic MAC [40, 43]
      Speed Strict population assumptions    
GPPH PP HA No PP Handles large datasets Theoretical Practical limit, biallelic MAC/PC/UNIX [40, 42]
      Speed Strict population assumptions    
HAPH IP HA/HF Yes HWE, IP Predicts haplotype blocks No probability for haplotype assignments Max 500 loci, Practical limit biallelic Web-based [44]
      Constructs
haplotypes within blocks 		    
      Identifies block
structure 		    
      Web-based     
Likelihood methods          
1. Maximum likelihood         
Arlequin v2.0 EM HA/HF No HWE Includes numerous population genetic analysis tools EM issues EM Practical Limits, biallelic/multiallelic JRE on MAC/PC/UNIX [89]
CHAPLIN ECM HF Yes HWE Graphical interface ECM algorithm needs to be compared with standard EM methods Practical limits, biallelic/multiallelic PC [91]
      Association tests     
      HWE assumption relaxed in case
sample 		    
EH EM HF No HWE Estimates haplotype frequency EM issues No Max, 3-4 practical max, biallelic/multiallelic PC [85, 104]
      Compares case-control HF
under different assumptions 		Must specify mode
of inheritance and
penetrance of disease 		   
EHPLUS EM HF No HWE Improves EH,
more loci and
polymorphic
markers 		Long run times
for permutation
calculations 		Max 5 loci,
15 alleles in
analysis 		PC/UNIX [84]
      Incorporates
model-free
analysis 		    
EM-DeCODER EM HA/HF No HWE Program with
standard EM
algorithm 		EM issues Max 15 loci,
biallelic 		UNIX [57]
FASTEHPLUS EM HF No HWE Similar to EHPLUS,
with speed
improvements 		EM issues Max 5 loci,
15 alleles in
analysis 		PC/UNIX [105]
GENECOUNTING EM HA/HF Yes HWE Provides posterior
probabilities
for assigned
haplotypes 		Missing data
limited to
biallelic loci 		10-15 loci
practical
limit, biallelic/
multiallelic 		PC/UNIX [106]
      Compares global
and specific
haplotypes
between groups 		EM issues    
GCHAP EM HA/HF YES HWE Haplotypes with
zero likelihood
dropped to
improve speed and
accuracy 		EM issues 20 loci practical
limit, biallelic 		JRE on
PC/UNIX 		[107, 108]
      Similar to SNPHAP     
GS-EM EM HA/HF Yes HWE Includes algorithm
for assigning probability to genotype
calls from several
genotyping
methods 		EM issues Practical limit,
biallelic 		Web-based [73]
      Haplotypes constructed using assigned genotypes probability Limited to biallelic SNPs    
      Web-based     
HAPZ EH HA/HF Yes HWE Modified version of
SNPHAP that
accommodates
multiallelic loci 		EM issues Practical limit, biallelic/multiallelic PC/UNIX [106]
HAPMAX MLE HF No HWE Ease of use Accommodates a limited number
of SNPs 		8 loci, biallelic PC [109]
       Interface    
HAPLOH EM HF Yes HWE Handles some missing data EM issues 10 loci, 40 alleles max, biallelic/multiallelic UNIX [47]
      Utilises pedigree data, if available     
      Calculates standard
error 		    
HAPLOSCOPE EM/MCMC † † † Platform program, incorporates SNPHAP and PHASE v1.0 See individual programs for limitations/features † UNIX/Windows [110]
      Facilitates
comparison/testing 		    
      Graphical interface, identifies tagging SNPs and LD
blocks 		    
HAPLOVIEW EM+PL HA/HF Yes HWE Calculates pairwise LD EM issues 100 s, practical limit, biallelic JRE on MAC/PC/UNIX [56]
      Checks for
recombination 		    
      Identifies tagging
SNPs 		    
      Accepts pedigree
and unrelated
genotype data 		    
HAPLO.STATS EM HA/HF Yes HWE Incorporates
method similar to
SNPHAP, with user
inputs 		Requires
knowledge of
S-Plus 6.0 or R 		Practical
limit, biallelic/
multiallelic 		S-PLUS
6.0 on
UNIX/R
on UNIX
& PC 		[86]
      Separate
programs that: 		EM issues    
      (1) assign
haplotypes with
posterior
probability of
assignments 		    
      (2) allow linear
regression for trait
to haplotype
analysis 		    
      (3) calculates score
statistic for haplotype phenotype
association 		    
HIT EM/MCMC/
MC+PL 		† † † Platform program,
incorporates
SNPHAP and
PHASE v1.0 		See individual
programs for
limitations/
features 		† * [111]
      Facilitates
comparison 		    
      Graphical interface,
identifies
tagging SNPs
and LD blocks 		    
HPLUS EM+EE+PL HA/HF Yes HWE Provides posterior
probabilities for
assigned haplotypes 		Requires Matlab 100 loci,
biallelic 		MATLAB
on PC/
UNIX 		[55, 83]
      Compares
haplotype
frequencies
between groups,
adjusts for
covariates 		EM issues    
      Utilises pedigree
data, if available 		    
LDSUPPORT EM HA/HF Yes HWE Provides posterior
probabilities for
assigned haplotypes 		EM issues * UNIX [29, 112]
      Identifies LD
blocks for
haplotype
reconstruction 		    
      Examines association with disease,
automation speeds
process 		    
LOGINSERM
ESTIHAPLO 		EM HA/HF Yes HWE Program uses ML
method to infer
haplotypes for individuals with missing
data 		EM issues Practical
limit, biallelic/multiallelic 		PC/
UNIX 		[80]
      Offers option to
exclude individuals
with missing data 		    
MLHAPFRE EM HF Yes HWE Performance improves with presence of LD Incorporated into Arlequin 16 loci, biallelic JRE on Mac/PC/UNIX [48]
      Performs well with
large sample size 		EM issues    
MLOCUS EM HA/HF Yes HWE Provides posterior probabilities for assigned haplotypes EM issues 11 loci, biallelic/multiallelic PC [46, 113]
      Notes observed vs.
inferred haplotypes 		    
      Calculates pairwise LD     
OSLEM EM Yes No HWE Modified EM algorithm that runs 2 × faster EM issues Practical limit, biallelic Web-based [114]
PL-EM EM+PL HA/HF Yes HWE Combines PL with EM EM issues 100 s, practical limit, biallelic PC/UNIX [54]
      EM-based version
of HAPLOTYPER 		    
      Calculates variance
of haplotype frequency estimates 		    
SAS Genetics EM HA/HF Yes HWE Provides posterior probabilities for assigned haplotypes Requires SAS Practical limit, biallelic/multiallelic SAS on PC/UNIX [115]
      Incorporates
statistical tests and
procedures 		EM issues    
SNPEM EM HF No HWE Estimates
haplotype
frequency by
population 		EM issues 10 loci, biallelic UNIX [10]
      Compares global
and specific
haplotype between
2 groups 		    
SNPHAP EM HA/HF Yes HWE Uses posterior and
prior trimming to
handle large
number loci 		EM issues Practical limit,
biallelic 		UNIX [52]
      Provides posterior
probabilities for
assigned haplotypes 		    
THESIAS S-EM HF Yes HWE Stochastic EM
avoids issues of
standard EM
programs 		S-EM algorithm
needs to be
compared with
standard EM
methods 		Practical limit,
20 loci,
biallelic 		PC/UNIX [53, 88]
      Includes tests for
haplotype-phenotype association 		    
      Accommodates
large sample sizes 		    
WHAP EM † † † Uses haplotype
output from
SNPHAP for
association testing 		EM issues † PC/UNIX [116]
      Allows weighted
association
analysis 		Requires
separate
haplotyping
program 		   
Zaykin et al. EM HF No HWE Program on
analysis of
haplotype-phenotype
association 		EM issues Practical
limit, biallelic/multiallelic 		PC/UNIX [82]
       Subjects with
missing data
ignored 		   
Zou and Zhao MLE/EM HF Yes HWE Adjust haplotype
frequency estimates for genotyping error 		Assumes genotyping errors are
random 		Practical limits,
biallelic/multiallelic 		* [68]
      Program also
works for nuclear
families 		Assumes error
rates are known 		   
3locus.PAS EM HF Yes HWE Handles some
missing data 		EM issues 3 loci, biallelic/
multiallelic 		PC/UNIX [46]
      Various tests
available 		    
      Improves with
increasing sample
size 		    
2. Simple Bayesian          
HAPLOTYPER MC+PL HA/HF Yes HWE Uses PL algorithm
to construct haplotypes with many
loci 		Long run times 256 max,
biallelic 		UNIX [57]
      Provides posterior
probabilities for
assigned haplotypes 		Posterior
probabilities may
be difficult to
interpret 		   
HAPLOREC MC-VL HA/HF Yes HWE Uses variable
length chain based
on maximising LD 		Restarts avoid
non-global
optimum 		Practical
limit,
biallelic 		Java
virtual
machine,
v1.4
or newer 		[62]
      Handles large
number loci 		    
3. Coalescent-based Bayesian e         
Arlequin v3.0 ELB HA/HF No Adaptive
window 		Includes numerous
population genetics
analyses 		Long run times 1,000 s, biallelic/
multiallelic 		JRE on
LINUX/
PC/Mac 		[60, 89]
      Handles recombination     
PHASE v2.0 MCMC+PL HA/HF Yes Coalescent/
HWE 		Improved run time Departure for
coalescent model
may impact performance 		Practical limit,
biallelic/
multiallelic 		PC/MAC/
UNIX 		[59]
      Compares haplotype frequency
between groups 		Posterior
probabilities may
be difficult to
interpret 		   
      Handles
recombination 		    
      Provides posterior
probabilities for
assigned haplotypes 		    
PHASE v1.0 MCMC HA/HF No Coalescent/
HWE 		Incorporates
pop-genetics and
coalescence ideas 		Departures for
coalescent model
may impact performance 		Practical limit,
biallelic/
multiallelic 		UNIX [51]
      Incorporates
known phase and
trios pedigrees into
analysis 		Slow run times    
      Provides posterior
probabilities for
assigned haplotypes 		Posterior probabilities
may be difficult
to interpret 		   
SLHAP v1.0 MCMC HA/HF Yes Neutral
coalescent/
HWE 		Similar to PHASE
v1.0 		Departures for
coalescent model
may impact performance 		Practical limit,
biallelic/multiallelic 		UNIX [58]
      Missing data     
      Improved run time     
  1. a Program haplotype output, individual assignment, frequency estimates or both.
  2. b Ability of program to accept missing data.
  3. c Program assumptions.
  4. d List of references.
  5. e Programs in this section make assumptions based on or draw inference from coalescent model.
  6. *Could not determine from available data.
  7. †See incorporated programs for features and limitations.
  8. EE: Estimating equation; ECM: Expectation conditional maximisation algorithm; ELB: Excoffier-Laval-Balding algorithm, Bayesian; EM: Expectation maximisation algorithm; EM issues: May be sensitive to HWE departures, long run times, and non-global max (requiring multiple restarts); HF: Haplotype frequency estimate; HA: Individual haplotype assignment; HWE: Hardy-Weinberg equilibrium; IP: Imperfect phylogeny-based method; JRE: Java runtime environment; LD: Linkage disequilibrium; MAC: Program runs on Apple computer; MC: Monte Carlo algorithm, Bayesian algorithm; MCMC: Markov Chain Monte Carlo algorithm, Bayesian algorithm; MC-VL: Monte Carlo-variable length chain algorithm, Bayesian Algorithm; MLE: Maximum likelihood estimation algorithm; PC: IBM compatible personal computer; PL: Partition ligation algorithm; PP: Perfect phylogeny-based method; Practical Limit: program has no upper limit on number of markers and/or subjects, however computational and practical considerations limit this value; S-EM: Stochastic EM algorithm; UNIX: Runs on Unix operating system, including Linux, FORTRAN, Solaris and others.
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Human Genomics

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