Program name | Algorithm | Outputa | Missing datab | Assumptionsc | Key features | Limitations | MAX subjects, loci and type | Platform | Ref.d |
---|---|---|---|---|---|---|---|---|---|
Parsimony methods | Â | Â | Â | Â | Â | Â | Â | Â | Â |
1. Simple parsimony | Â | Â | Â | Â | Â | Â | Â | Â | Â |
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 | Â | Â | Â | Â | Â | Â | Â | Â | Â |
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 | |
 |  |  |  |  | Speed | Strict population assumptions |  |  |  |
GPPH | PP | HA | No | PP | Handles large datasets | Theoretical | Practical limit, biallelic | MAC/PC/UNIX | |
 |  |  |  |  | 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 | Â | Â | Â | Â | Â | Â | Â | Â | Â |
1. Maximum likelihood | Â | Â | Â | Â | Â | Â | Â | Â | |
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 | |
 |  |  |  |  | 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 | |
 |  |  |  |  | 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 | |
 |  |  |  |  | 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 | |
 |  |  |  |  | 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 | |
 |  |  |  |  | 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 | |
 |  |  |  |  | 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 | Â | Â | Â | Â | Â | Â | Â | Â | Â |
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 | Â | Â | Â | Â | Â | Â | Â | Â | |
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 | |
 |  |  |  |  | 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 |  |  |  |  |