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R package for the identification of cancer-associated mutated genes using gene expression and mutation data.

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# TDAmut
R package for the identification of cancer-associated mutated genes using gene expression and mutation data.

Rabadan R., Mohamedi Y., Rubin U., Chu T., Alghalith A. N., Elliott O., Arnes L., Cal S., Obaya A. J., Levine A. J., and Camara P. G., _"Identification of Relevant Genetic Alterations in Cancer using Topological Data Analysis"_. Nature Communications 11 (2020) 3808. [DOI: 10.1038/s41467-020-17659-7](https://doi.org/10.1038/s41467-020-17659-7).

Using TDAmut to analyze low grade glioma data
================

*Updates to this tutorial are ongoing. What follows displays a near-complete workflow for using this package.*

## Getting Started

We will use low grade glioma expression and mutation data to demonstrate
the TDAmut pipeline. The sample data is formatted from publically
available TCGA data and is provided in the `TDAmut` package. Expression
data is assumed to be normalized data (e.g. \(log_2[1+TPM]\)) formatted
as a matrix (rows = samples, columns = genes). Mutation data is assumed
be in a table organized by *Sample*, *Gene*, and *Type* (e.g. missense,
nonsense, splice, frameshift, …).

The user is afforded several options in each function of `TDAmut`. We
implemented default options which can be a helpful starting point for
the user.

Install and load `TDAmut`:

``` r
devtools::install_github("CamaraLab/TDA-TCGA")
library(TDAmut)
```
Note that this package requires prior installation of additional packages not available via CRAN (e.g., bioDist from BioConductor, RayleighSelection from the CamaraLab GitHub) in order to succeed. If these packages are not currently available on your system, they will need to be installed prior to installing the `TDAmut` package.

## Creating TDAmut object for use throughout the pipeline

`TDAmut` takes as input the gene expression matrix and mutation table of the tumor cohort. The expected format for these two files can be seen in the example
files in the folder `data`. The first step in the `TDAmut` pipeline is to create a `TDAmut` object. The `TDAmut` object is used as an intermediate across all functions
and holds data and topological representations produced in this pipeline.

``` r
exp_data_path <- "data/LGG_Full_TPM_matrix.csv"
mut_data_path <- "data/LGG_Muts.txt"
LGG_object <- create_TDAmut_object(exp_data_path, mut_data_path)
```

``` lim-message
## Removed 305 genes with no expression data
```

``` lim-message
## Removed samples in expression data not in mutation data: 'TCGA-DU-7014-01A', 'TCGA-DU-A7TI-01A', 'TCGA-HW-7493-01A', 'TCGA-TQ-A7RK-02B'
```

``` lim-message
## The following genes have mutation data but no expression data. They will not be considered for filtering of negative correlations later in the TDAmut pipeline: 'LEPREL1.55214', 'KRTAP21-2.337978', 'MT-ND4.4538', 'HLA-DRA.3122', 'KAL1.3730', 'MT-ND5.4540', 'MT-CO1.4512', 'MT-CO3.4514', 'ZRSR1.7310', 'C14orf182.283551', 'HLA-DQB2.3120', 'GPR124.25960', 'GPR98.84059', 'KRTAP4-6.81871', 'HLA-DMB.3109', 'OR9G1.390174', 'FSIP2.401024', 'OR2T7.81458', 'FRG1B.284802', 'FRMPD3.84443', 'C12orf36.283422', 'HLA-DQA2.3118', 'NKX2-1.7080', 'KRTAP1-5.83895', 'ANKRD36C.400986', 'MT-CYB.4519', 'HLA-C.3107', 'KRTAP4-11.653240', 'KRTAP17-1.83902', 'CNTNAP3B.728577', 'KIAA1045.23349', 'GCN1L1.10985', 'HLA-F.3134', 'KRTAP4-4.84616', 'KRTAP9-9.81870', 'KRTAP19-1.337882', 'KRTAP10-5.386680', 'KRTAP4-2.85291', 'GPR112.139378', 'KRTAP10-3.386682', 'LPHN3.23284', 'KRTAP13-1.140258', 'KRTAP10-12.386685', 'HLA-A.3105', 'GPR110.266977', 'FAM115C.285966', 'UBBP4.23666', 'NPIPA5.100288332', 'HIST1H4G.8369', 'ZNF812.729648', 'NKX2-2.4821', 'AKR1CL1.340811', 'BAI1.575', 'SLC9B1P1.100128190', 'KRTAP4-8.728224', 'CCDC132.55610', 'EBLN1.340900', 'KRTAP12-4.386684', 'CXorf22.170063', 'GPR115.221393', 'FAM178A.55719', 'GPR125.166647', 'AC073343.1.0', 'C4B.721', 'EMR1.2015', 'WDR16.146845', 'HEATR2.54919', 'NBPF20.100288142', 'MYZAP.100820829', 'OR5H15.403274', 'KRTAP19-2.337969', 'LPHN2.23266', 'CHDC2.286464', 'TTC6.319089', 'KIAA1377.57562', 'ERO1LB.56605', 'MUC5AC.4586', 'KRTAP4-9.100132386', 'OR1D5.8386', 'KIAA1279.26128', 'SMEK1.55671', 'GPR111.222611', 'KIAA1244.57221', 'ZNF852.285346', 'C17orf70.80233', 'KRTAP10-10.353333', 'LEPRE1.64175', 'C1orf86.199990', 'KRTAP4-7.100132476', 'FAM154B.283726', 'FPGT-TNNI3K.100526835', 'GPR116.221395', 'DAK.26007', 'GPR128.84873', 'OTOGL.283310', 'EMR2.30817', 'HLA-DPB1.3115', 'LOC101929950.101929950', 'KRTAP5-2.440021', 'PCDHB17.54661', 'PLA2G4B.100137049', 'NHP2L1.4809', 'TMEM189-UBE2V1.387522', 'ANKRD32.84250', 'GPR113.165082', 'HLA-DMA.3108', 'KRTAP4-3.85290', 'GPR97.222487', 'C6orf211.79624', 'TSSK2.23617', 'C7orf55-LUC7L2.100996928', 'LPHN1.22859', 'MUC3A.4584', 'TENC1.23371', 'HLA-E.3133', 'CCDC180.100499483', 'HLA-DRB1.3123', 'FAM154A.158297', 'GPR133.283383', 'B3GALTL.145173', 'GPR126.57211', 'PTPLAD2.401494', 'KRTAP5-4.387267', 'GPR64.10149', 'KRBOX1.100506243', 'RP11-467N20.5.0', 'CCL4L1.9560', 'PTGES3L.100885848', 'C5orf55.116349', 'TMEM194A.23306', 'SMEK2.57223', 'KRTAP10-7.386675', 'KRTAP9-8.83901', 'KRTAP1-1.81851', 'KRTAP9-2.83899', 'DEFA3.1668', 'KRTAP10-6.386674', 'ZFYVE20.64145', 'AGAP10.728127', 'KRTAP5-3.387266', 'IQCJ-SCHIP1.100505385', 'PRAMEF7.441871', 'HIST1H2AA.221613', 'KRTAP9-1.728318', 'ERO1L.30001', 'TCEB3CL2.100506888', 'IGJ.3512', 'KRTAP10-2.386679', 'ZNF724P.440519', 'FOLR4.390243', 'TMEM256-PLSCR3.100529211', 'ZNF587B.100293516', 'TRIM49C.642612', 'DEFB113.245927', 'KRTAP5-1.387264', 'EMR3.84658', 'KRTAP10-1.386677', 'NCBP2L.392517', 'NKX3-1.4824', 'NPIPB4.440345', 'OR5I1.10798', 'RP11-166B2.1.0', 'NMS.129521', 'KRTAP5-8.57830', 'NPIPA8.101059953', 'GOLGA6L2.283685', 'CD97.976', 'KRTAP10-8.386681', 'RNF223.401934', 'C2orf43.60526', 'MT-CO2.4513', 'ELTD1.64123', 'ERVW-1.30816', 'HLA-DOA.3111', 'RBAK-RBAKDN.100533952', 'GOLGA8I.283796', 'ZNF783.100289678', 'UGT2B17.7367', 'HLA-DRB5.3127', 'KRTAP20-2.337976', 'NPIPB11.728888', 'GOLGA6L3.100133220', 'KRTAP21-1.337977', 'OPN1MW2.728458', 'KRTAP4-5.85289', 'WASH4P.374677', 'ZNF728.388523', 'FAM47E-STBD1.100631383', 'TRIM73.375593', 'OR52B1P.81274', 'IGHV3OR16-9.28307', 'MTPN.136319', 'RBMY1E.378950', 'NUTM2E.283008', 'MS4A4E.643680', 'OR4C5.79346', 'OR14K1.343170', 'HLA-DQA1.3117', 'CT47A6.728062', 'KRTAP5-5.439915', 'C11orf72.100505621', 'KRTAP10-9.386676', 'KRTAP11-1.337880', 'RP11-146E13.4.0', 'TRAV9-2.28677', 'OTX2-AS1.100309464', 'LINC00969.440993', 'MT-ND2.4536', 'KRTAP9-3.83900', 'HLA-DRB6.3128', 'DAOA-AS1.282706', 'DNM1P47.100216544', 'RP11-423O2.5.0', 'LOC728339.728339', 'RP11-254I22.1.0', 'SNHG24.101929369', 'LINC00854.100874261', 'LOC727993.727993', 'MIR646HG.284757', 'AC027612.3.0', 'LOC63930.63930', 'IGHG1.3500', 'TUBB8P7.197331', 'MIR146A.406938', 'RP11-308D16.4.0', 'CTC-535M15.2.0', 'CCDC175.729665', 'TRGC2.6967', 'IGHA1.3493', 'KRT17P2.339241', 'RP11-739N20.2.0', 'RP11-686D16.1.0', 'OVOS2.144203', 'RP11-847H18.2.0', 'GOLGA6L17P.642402', 'SNHG14.104472715', 'LOC101928372.101928372', 'LOC400800.400800', 'FLJ16171.441116', 'NOS2P1.645740', 'SOX9-AS1.400618', 'SLC9A7P1.121456', 'TRAV8-2.28684', 'NANOGP1.404635', 'LOC101927905.101927905', 'IGLV3-12.28802', 'BAI3.577', 'HERC2P3.283755', 'KRT19P2.160313', 'LOC101927533.101927533', 'MIR381HG.378881', 'RP11-156P1.3.0', 'LINC00971.440970', 'TAPT1-AS1.202020', 'IGHV1OR16-3.28313', 'NUTM2B-AS1.101060691', 'HLA-V.352962', 'KIZ-AS1.101929591', 'IGHV4-28.28400', 'RP11-89K10.1.0', 'IGHV3-33.28434', 'RP11-1028N23.4.0', 'AC015849.16.0', 'RP11-625I7.1.0', 'ZNF503-AS1.253264', 'GNAS-AS1.149775', 'IGHD.3495', 'RP11-149P24.1.0', 'RP11-221N13.4.0', 'IGKV3D-20.28874', 'LINC00987.100499405', 'APCDD1L-AS1.149773', 'LLNLF-65H9.1.0', 'RP11-464F9.1.0', 'LINC00477.144360', 'RP11-807H22.7.0', 'RP11-122F24.1.0', 'ROCK1P1.727758', 'WASH6P.653440', 'RPL12P38.645688', 'BCRP2.400892', 'RP11-85G18.6.0', 'HNRNPKP3.399881', 'RP11-556I14.1.0', 'ZNRD1-AS1.80862', 'IGLV2-28.28812', 'MIR3687-2.103504728', 'LOC101927209.101927209', 'RP11-435B5.5.0', 'LOC101927755.101927755', 'MED15P9.285103', 'LOC403323.403323', 'GAPDHP15.642317', 'HCG17.414778', 'IGHG3.3502', 'H3F3AP4.440926', 'LOC101927079.101927079', 'RP11-504G3.4.0', 'RP11-252A24.2.0', 'UPF3AP2.147150', 'MRPS31P5.100887750', 'IGHG4.3503', 'CTB-134H23.3.0', 'HERC2P9.440248', 'IGLC3.3539', 'TRBV6-8.28599', 'TRBV5-4.28611', 'PBX2P1.5088', 'EIF4E2P2.645207', 'TRDV2.28517', 'UBA6-AS1.550112', 'LOC442028.442028', 'CCT6P3.643180', 'RP11-24M17.5.0', 'KTN1-AS1.100129075', 'LOC100288069.100288069', 'CTD-2251F13.1.0', 'RP11-433J8.2.0', 'MIR371B.100616185', 'LOC105371814.105371814', 'CTC-548K16.2.0', 'NDUFA6-AS1.100132273', 'CTC-260E6.6.0', 'LOC643201.643201', 'TBC1D3P3.653017', 'LRRC37A11P.342666', 'AC016995.3.0', 'KANTR.102723508', 'DPPA3P2.400206', 'RP11-44F14.1.0', 'ANKRD20A5P.440482', 'RP11-114H23.1.0', 'RP11-652G5.1.0', 'RP11-404F10.2.0', 'TRBV29-1.28558', 'IGHV1-18.28468', 'CTB-161M19.4.0', 'INTS4L2.644619', 'RP11-597A11.6.0', 'IGLV7-43.28776', 'TRBV6-7.28600', 'SRGAP2-AS1.100873165', 'IGHV3-38.28429', 'TRAV24.28659', 'SRGAP2B.647135', 'IGHV1-58.28464', 'RP5-991G20.1.0', 'XXbac-BPG308J9.3.0', 'IGHE.3497', 'RP11-324C10.1.0', 'IGHV3-11.28450', 'IGHV3-20.28445', 'RP11-608O21.1.0', 'GPR123.84435', 'RP11-782C8.1.0', 'TRBV19.28568', 'IGHV4OR15-8.28317', 'IGHV3-49.28423', 'MIR377.494326', 'TRAJ57.28698', 'GPR56.9289', 'TRAV41.28640', 'SPINT4.391253', 'SNORD113-3.767563', 'MIR181A1.406995', 'TRAV27.28655', 'MAP3K14-AS1.100133991', 'MIR506.574511', 'TP73-AS1.57212', 'TRIM51HP.440041', 'IGLV2-23.28813', 'C20orf166-AS1.253868', 'IGHV3-72.28410', 'IGHV7-81.28378', 'MIR101-1.406893', 'TRBV4-1.28617', 'MIR380.494329', 'EMR4P.326342', 'IGKV6D-21.28870', 'SNORD114-31.767612', 'MIR518F.574472', 'TRBV6-5.28602', 'IGHV5-51.28388', 'TRBV6-1.28606', 'MIR518A1.574488', 'KRTAP9-4.85280', 'TRAV38-2DV8.28643', 'IGLV8-61.28774', 'IGKV3-20.28912', 'ATF4P4.100127952', 'IGHV3OR15-7.28318', 'HLA-B.3106', 'KIAA1598.57698', 'KRT16P2.400578', 'TRAV17.28666', 'MIR519A2.574500', 'HLA-F-AS1.285830', 'TRDJ1.28522', 'LEPREL2.10536', 'RPLP0P6.220717', 'PCDHB18.54660', 'IGLV3-16.28799', 'ZNF271.10778', 'TRBV11-1.28582', 'KRTAP5-9.3846', 'IGLV2-14.28815', 'TRBC2.28638', 'BAI2.576', 'IGKJ5.28946', 'RP11-337C18.8.0', 'FAIM3.9214', 'FAM21EP.100421577', 'IGHV1-45.28466', 'MIR509-1.574514', 'TRAV26-1.28657', 'IGHV1-24.28467', 'IGHV4-59.28392', 'MIR96.407053', 'IGHG2.3501', 'IGKV1-12.28940', 'LINC00842.643650', 'LRRC53.100144878', 'IGLV6-57.28778', 'BGLT3.103344929', 'TRAV18.28665', 'MIR517A.574479', 'CHEK2P2.646096', 'TRGV9.6983', 'TRDC.28526', 'MIR548A1.693125', 'IGLV11-55.28770', 'TRAV3.28690', 'TBC1D3P5.440419', 'TRGC1.6966', 'PPP1R2P1.100507444', 'IGLV2-18.28814', 'TRBV5-1.28614', 'RP11-156P1.2.0', 'IGLV4-3.28786', 'MIR450A1.554214', 'LOC100507291.100507291', 'LOC101927126.101927126', 'RP11-399K21.11.0', 'TRAV21.28662', 'LINC01500.102723742', 'RP11-439I14.2.0', 'TRBV7-6.28592', 'IGLV5-37.28783', 'TRBV6-6.28601', 'PDPK2P.653650', 'RP11-353N4.5.0', 'GLUD1P2.100381203', 'RP11-67H24.2.0', 'RP13-329D4.3.0', 'KRTAP12-2.353323', 'RP11-271K11.5.0', 'LA16c-23H5.4.0', 'IL9RP3.729486', 'MT1HL1.645745', 'MIR548I2.100302277', 'ZNRF2P2.100271874', 'FAM66B.100128890', 'IGLV1-40.28825', 'HIST2H2BB.338391', 'IGHV3-64.28414', 'LINC00639.283547', 'NUP210P1.255330', 'KRTAP15-1.254950', 'BNIP3P1.319138', 'AC005013.5.0', 'STARD7-AS1.285033', 'AC009120.6.0', 'KRTAP12-1.353332', 'LINC00886.730091', 'KRTAP5-11.440051', 'LOC100130700.100130700', 'TRBV10-2.28584', 'IGLV7-46.28775', 'MIR30B.407030', 'SPACA6P-AS.102238594', 'LINC01597.400841', 'RP11-991C1.2.0', 'RNA5-8SP6.100873336', 'IGLV3-25.28793', 'IGHV3-30.28439', 'LOC101926911.101926911', 'TRBV10-1.28585', 'BSNDP4.106481726', 'NKX2-8.26257', 'AL132989.1.0', 'MIR297.100126354', 'GPR42.2866', 'IGLV3-22.28795', 'AP001347.6.0', 'RP11-159L20.2.0', 'IGHV3-43.28426', 'LINCMD1.101154644', 'RP11-13J8.1.0', 'LRRC37A5P.652972', 'RP11-21G20.3.0', 'ACN9.57001', 'RP11-377D9.3.0', 'ZNF528-AS1.102724105', 'RP11-344E13.3.0', 'MIR517C.574492', 'MTHFD2P1.100287639', 'LOC101927460.101927460', 'LOC101926941.101926941', 'LINC01158.100506421', 'LRCOL1.100507055', 'KRTAP5-10.387273', 'PROX1-AS1.100505832', 'ZNF730.100129543', 'TPTE2P2.644623', 'MIR9-2.407047', 'RP11-340I6.7.0', 'RASA4B.100271927', 'LOC100506457.100506457', 'LOC105373525.105373525', 'CTD-2185K10.1.0', 'CTC-436P18.1.101928630', 'RP11-239H6.2.0', 'RP3-428L16.1.0', 'RP11-27P7.1.0', 'KB-1615E4.2.0', 'KB-1507C5.4.0', 'RP11-1113L8.1.0', 'LOC440446.440446', 'LINC01476.101927728', 'LINC00229.414351', 'LOC101928627.101928627', 'MIR337.442905', 'RP1-241P17.4.0', 'TRBV11-2.28581', 'RP11-640M9.2.0', 'CTD-2296D1.4.0', 'IGHV1OR15-9.390531', 'RP11-51L5.5.0', 'IGHV3-48.28424', 'LOC101928663.101928663', 'RP11-114H24.4.0', 'RP11-478C19.2.0', 'MIR892A.100126342', 'LOC400867.400867', 'LOC283683.283683', 'GS1-124K5.2.0', 'AZGP1P1.646282', 'LINC01359.101927084', 'LOC101927237.101927237', 'LOC101927708.101927708', 'AC073321.4.0', 'MIR663AHG.284801', 'RP11-597A11.1.0', 'IGKV1-6.28943', 'MIR7162.102466227', 'KRTAP10-11.386678', 'RP11-1082L8.3.0', 'RPL34-AS1.285456', 'RP11-526A4.1.0', 'CCNB3P1.100131678', 'RP11-436D23.1.0', 'RP11-314D7.1.0', 'LOC101243545.101243545', 'LOC100507377.100507377', 'TRGV4.6977', 'CTC-512J12.4.0', 'AC018359.1.0', 'CTD-2269F5.1.0', 'KRT223P.643115', 'MIR520E.574461', 'AC007251.2.0', 'RP11-390F4.6.0', 'AC012322.1.0', 'RP11-483E23.2.0', 'RNA5-8SP2.100873571', 'HLA-DOB.3112', 'MIR522.574495', 'PTPLAD1.51495', 'SMURF2P1.0', 'NPIPB1P.729602', 'DNM1P34.729809', 'TRBV7-3.28595', 'LINC00202-2.731789', 'KRT16P6.353194', 'IGKV5-2.28907', 'LINC01378.103689918', 'SUDS3P1.285647', 'GOLGA2P9.440518', 'IL12A-AS1.101928376', 'CYP21A1P.1590', 'LOC101927648.101927648', 'RP11-19N8.4.0', 'C1orf85.112770', 'LINC01239.441389', 'IGLV1-50.28821', 'AP001604.3.0', 'OR10J8P.343409', 'RP11-178C3.1.0', 'LINC01250.101927554', 'HSPD1P6.645548', 'IGHV2-26.28455', 'LINC01122.400955', 'LINC01229.101928248', 'RP11-493L12.5.0', 'LINC00499.100874047', 'LINC00621.100996930', 'IGKV1D-17.28900', 'LIPE-AS1.100996307', 'SMPD4P1.645280', 'LOC101928553.101928553', 'LOC100507053.100507053', 'OR8G1.26494', 'TRGV3.6976', 'SLC2A1-AS1.440584', 'KRTAP19-8.728299', 'PINLYP.390940', 'SMG1P7.100506060', 'LOC101927575.101927575', 'RP11-274B21.1.0', 'MEF2C-AS1.101929423', 'DUXAP8.503637', 'LINC01269.103695436', 'LOC101927040.101927040', 'TRDV1.28518', 'TRBV6-4.28603', 'SNHG23.100507242', 'CTC-338M12.9.0', 'CTD-2184D3.5.0', 'FAM74A7.100996582', 'SNORD3C.780853', 'LOC728715.728715', 'ANKRD30BP3.338579', 'RP11-93K22.13.0', 'CTC-439O9.3.0', 'LOC101928880.101928880', 'TRBV7-1.28597', 'RP11-1166P10.6.0', 'RP1-167F1.2.0', 'LOC101928940.101928940', 'RP11-25I15.2.0', 'LOC100289333.100289333', 'RP11-180I4.2.0', 'IGLV5-45.28781', 'IGHD3-10.28499', 'GOLGA6L7P.728310', 'IGHV3-13.28449', 'SNAP25-AS1.100131208', 'IGHV4-61.28391', 'IGHV3OR16-8.388255', 'CSAG4.100130935', 'RP11-418J17.3.0', 'CTD-2377D24.8.0', 'LOC101929350.101929350', 'KRTAP13-3.337960', 'IGKV6D-41.28869', 'GRIFIN.402635', 'SDCCAG3P1.388478', 'RP5-963E22.4.0', 'LOC101929066.101929066', 'CTD-2066L21.3.0', 'CTD-3092A11.1.0', 'SRP54-AS1.100506157', 'ANKRD20A2.441430', 'LOC100505782.100505782', 'USP32P3.347716', 'IGHV3-53.28420', 'STEAP2-AS1.100874100', 'LINC00674.100499466', 'IGHA2.3494', 'CTD-2245F17.3.0', 'IGHM.3507', 'LOC100420587.100420587', 'LOC642426.642426', 'NKX3-2.579', 'SVILP1.645954', 'LOC100287072.100287072', 'INTS4L1.285905', 'RP11-451O13.1.0', 'RP11-383M4.6.0', 'QRSL1P2.100422330', 'RP11-481J13.1.0', 'TRGV2.6974', 'IGKV1D-16.28901', 'RP11-586K2.1.0', 'SORD2P.653381', 'RP11-645C24.5.0', 'TRAV12-2.28673', 'RP13-228J13.1.0', 'SDAD1P1.157489', 'IGHV1OR16-2.28314', 'AC006988.1.0', 'ISX-AS1.101926957', 'RP11-587D21.4.0', 'LINC01317.104355287', 'LINC00459.100874180', 'IGKV1D-12.28903', 'LINC00202-1.387644', 'TRBV3-1.28619', 'MIR34A.407040', 'RP11-170M17.1.0', 'TRAV7.28686', 'IGHV3-21.28444', 'CYP4F24P.388514', 'TBC1D27.96597', 'LINC00359.100887754', 'LINCR-0001.101929191', 'NIFKP6.100132796', 'CTC-559E9.6.0', 'CTC-513N18.6.0', 'RP11-20E24.1.0', 'TRAJ24.28731', 'ANKRD20A18P.391269', 'LINC00877.285286', 'RP11-161I6.2.0', 'MIR494.574452', 'IGKV1D-8.28904', 'RP11-782C8.2.0', 'AC002331.1.0', 'RP11-796E2.4.0', 'AC005077.5.0', 'FAM177A1P1.728710', 'LOC101928782.101928782', 'MIR24-2.407013', 'MIR940.100126328', 'LOC100289656.100289656', 'EMC3-AS1.442075', 'RP11-431K24.1.0', 'IGHJ6.28475', 'RP11-525A16.4.0', 'MT-ND6.4541', 'IGHV1-46.28465', 'LINC01076.106144602', 'LL22NC03-86D4.1.105373010', 'KRTAP5-6.440023', 'IGHV3-16.28447', 'RP11-509A17.3.0', 'AP000320.7.0', 'RP11-519G16.3.0', 'ERICH1-AS1.619343', 'CTB-35F21.1.0', 'RP5-905H7.3.0', 'SNORD3B-1.26851', 'TRBV9.28586', 'RP11-23E10.4.0', 'RP11-556N21.1.0', 'IGHV1OR21-1.390530', 'RP11-206L10.10.0', 'RP11-35J10.5.0', 'MIR508.574513', 'LOC100132077.100132077', 'CTD-2532D12.4.0', 'TRBV20-1.28567', 'NPIPB6.728741', 'COX10-AS1.100874058', 'KRT17P4.339186', 'TRAV13-1.28671', 'TRBV6-9.28598', 'RP1-30E17.2.0', 'IGKV2D-29.28882', 'TRBV28.28559', 'TBC1D3P1-DHX40P1.653645', 'MIR526B.574468', 'TRBV5-7.28608', 'LOC101928823.101928823', 'LINC00511.400619', 'KRTAP10-4.386672', 'RP11-275O4.3.0', 'CPHL1P.389160', 'LOC105375875.105375875', 'RP11-260M19.2.0', 'TRAV19.28664', 'HIST2H3PS2.440686', 'LINC00857.439990', 'TRBV27.28560', 'LINC01331.104310351', 'MRPL42P4.346470', 'RP11-420N3.2.0', 'IGLV9-49.28773', 'CTD-2503O16.4.0', 'SPDYE18.100505767', 'LOC643542.643542', 'RPL39P5.553117', 'CHORDC2P.317775', 'RP11-3P22.2.0', 'CCRN4L.25819', 'IGHV1OR16-4.28312', 'TRBV7-7.28591', 'RP11-649A16.1.0', 'AL133247.2.0', 'LOC100287934.100287934', 'RP11-1060J15.4.0', 'HMGB3P5.645360', 'TUBBP1.92755', 'IGKV1-16.28938'
```

``` r
LGG_object@expression_table[1:5, 1:5]
```

##                  A1BG.AS1.503538 A1BG.1 A1CF.29974 A2M.AS1.144571  A2M.2
    ## TCGA-CS-4938-01B          2.7407 2.4365          0         0.4432 8.9506
    ## TCGA-CS-4941-01A          1.6222 2.3834          0         1.7243 9.4713
    ## TCGA-CS-4942-01A          2.0342 2.4167          0         0.3698 9.3009
    ## TCGA-CS-4943-01A          1.5353 1.4604          0         0.3816 8.7217
    ## TCGA-CS-4944-01A          0.9567 1.0011          0         0.4874 8.2942

``` r
LGG_object@mutation_table[1:5, ]
```

##             Sample           Gene Mutation              Type
    ## 1 TCGA-CS-4938-01B    PRPF8.10594 p.R1141C Missense_Mutation
    ## 2 TCGA-CS-4938-01B       TPO.7173  p.G712S Missense_Mutation
    ## 3 TCGA-CS-4938-01B RPS19BP1.91582  p.K115E Missense_Mutation
    ## 4 TCGA-CS-4938-01B      FGF5.2250  p.R205G Missense_Mutation
    ## 5 TCGA-CS-4938-01B    KDM7A.80853  p.S318R Missense_Mutation

## Creating topological representations of expression data

The `LGG_object` is passed to compute\_complexes, which uses TDAmapper
and RayleighSelection R packages to create nerve complexes across a grid
of Mapper parameters (2D intervals and their percent overlap). We create
several nerve complexes across a broad range of parameters to ensure
stable results.

The `LGG_object` is populated with the topological representations and
the parameters used to make
them.

``` r
LGG_object <- compute_complexes(LGG_object, filter_method = 'KNN', k = 30, min_interval = 10, max_interval = 60, interval_step = 10, min_percent_overlap = 60, max_percent_overlap = 85, percent_step = 5)
```

## Assessing current results by visualizing topological representations

To check the validity of the options chosen in the pipeline so far, we
want to visualize our data on the topological representations. We expect
to see localization of mutated genes which have been previously
identified as distinct markers of low grade glioma subtypes.

- IDH1 mutations in a subtype of astrocytoma
  - ATRX mutations in a astrocytic gliomas
  - CIC mutations in oligodendromas

We’ve chosen the topological representation created with 2D intervals =
30 and percent overlap = 75. More can be specified in a vector of
interval and percent pairs passed to `which_complexes`. By default, 3
representations with parameters in the middle of the parameter range are
chosen.

``` r
LGG_genes <- c('EGFR.1956', 'TP53.7157', 'IDH2.3418', 'CIC.23152')

plot_mapper(LGG_object, type = 'mutation', features = LGG_genes, which_complexes = c(30,75))
```

## Plotting nerve complex with 2D intervals = 30 and percent overlap = 75

*Images to be added soon*

## Filtering genes by mutation frequency, highest fraction of nonsynonymous mutations, and weak correlations between expression and mutation data

Genes can be filtered by

- Mutational frequency among all samples
  - Those with the greatest ratio of nonsynonymous mutations to total
    mutations
  - Associations between expression and mutation rates of a gene

For example, anticorrelations between expression and mutation rates can
arise due to transcription-coupled DNA repair. To correct for this, we
assess the similarity of expression and mutation profiles within the
topological representations using Spearman's rank correlation coefficient.

Genes with a median q value in between the thresholds specified by the
`upper_correlations_threshold` and `lower_correlations_threshold` arguments 
are not considered, as they do not display a strong correlation or 
anticorrelation between expression and mutation rates.

``` r
LGG_object <- filter_genes(LGG_object, freq_threshold = 0.015, top_nonsyn_fraction = 350, upper_correlations_threshold = 0.9, lower_correlations_threshold = 1e-4)
```

## Not considering the following genes with no expression data: 'ANKRD36C.400986', 'FRG1B.284802', 'GPR112.139378', 'GPR98.84059', 'HLA-A.3105', 'HLA-DQB2.3120', 'KRTAP1-5.83895', 'KRTAP4-11.653240', 'KRTAP4-8.728224', 'KRTAP4-9.100132386', 'NPIPA5.100288332', 'UBBP4.23666'
    
    ## Not considering the following 93 genes not displaying strong correlations/anticorrelations between mutation and expression data: 'ABCA7.10347', 'ACAN.176', 'ADAM28.10863', 'ADAMTS9.56999', 'AHNAK.79026', 'ARID1A.8289', 'ASPM.259266', 'BOD1L1.259282', 'CACNA1E.777', 'CD163L1.283316', 'CD209.30835', 'CELSR3.1951', 'CHD9.80205', 'CLIP1.6249', 'COL7A1.1294', 'CPAMD8.27151', 'CSF2RA.1438', 'CSMD3.114788', 'DCAF12L2.340578', 'DCP1B.196513', 'DMBT1.1755', 'DMD.1756', 'DNAH17.8632', 'DNAH7.56171', 'DNAH8.1769', 'DNMT3A.1788', 'DOCK5.80005', 'DRC7.84229', 'F5.2153', 'F8.2157', 'FAT4.79633', 'FBN2.2201', 'FLG.2312', 'FRAS1.80144', 'FSTL5.56884', 'HECTD4.283450', 'HIVEP3.59269', 'HRNR.388697', 'HTR3A.3359', 'IDH1.3417', 'IDH2.3418', 'IGF1R.3480', 'IL32.9235', 'KCNN2.3781', 'KIF16B.55614', 'KIF2B.84643', 'KMT2A.4297', 'LAMA3.3909', 'LRP1.4035', 'LRP1B.53353', 'LRP2.4036', 'LRRK1.79705', 'MAML3.55534', 'MUC5B.727897', 'MYH1.4619', 'MYH11.4629', 'MYH13.8735', 'MYH4.4622', 'MYO15A.51168', 'NBPF1.55672', 'NBPF10.100132406', 'NEB.4703', 'OGT.8473', 'PCDH19.57526', 'PCDHA2.56146', 'PCDHB3.56132', 'PCLO.27445', 'PDGFRA.5156', 'PHF3.23469', 'PKHD1.5314', 'PLEC.5339', 'PLXNA1.5361', 'POTEC.388468', 'PRDM9.56979', 'PTPRZ1.5803', 'RANBP2.5903', 'RELN.5649', 'RGAG1.57529', 'RIPK4.54101', 'ROBO3.64221', 'ROS1.6098', 'RYR1.6261', 'RYR2.6262', 'SETD2.29072', 'SPATA31E1.286234', 'TENM1.10178', 'TMEM132B.114795', 'TNXB.7148', 'TRRAP.8295', 'TTN.7273', 'VPS13B.157680', 'WDFY3.23001', 'ZNF638.27332'

## Assessing localization of filtered genes

Filtered genes are assessed for localization across the topological
representations using `RayleighSelection`. Localization is quantified
via a p value, estimated by a similar permutation scheme as noted above.
The false discovery rate is controlled using the Benjamini-Hochberg
procedure, which results in an accompanying localization q value.

Note: `compute_gene_localization` is the most time-intensive function 
of `TDAmut` and can take a couple hours. Consider using the `num_cores` 
argument to parallelize this function.

``` r
LGG_object <- compute_gene_localization(LGG_object, num_permutations = 5000, num_cores = 1)
```

Results are summarized and stored in the `summary_matrix` slot of the
TDAmut_object. Genes with a median localization q value below a 
user-defined threshold should be considered significant. These genes 
are predicted to be associated with global expression patterns over a 
subset of tumors.

``` r
LGG_object@summary_matrix[1:8,]
```

##              combined.p0           q0 expression_first_quartile expression_median expression_third_quartile cor_median_p cor_median_q cor_median_rho nonsyn_count
    ## ATRX.546    0.000000e+00 0.0000000000                  3.060450           3.72140                  4.425275 2.146322e-76 5.172635e-74     -0.7005306          204
    ## CIC.23152   0.000000e+00 0.0000000000                  4.821300           5.16165                  5.496125 4.439870e-61 5.350044e-59     -0.6486133          113
    ## EGFR.1956   0.000000e+00 0.0000000000                  4.331775           5.32795                  6.205900 1.000000e+00 1.000000e+00      0.3216203           36
    ## FUBP1.8880  0.000000e+00 0.0000000000                  4.586700           5.03025                  5.417500 9.635606e-30 7.641520e-28     -0.4790635           48
    ## NF1.4763    0.000000e+00 0.0000000000                  4.817325           5.15865                  5.509025 3.979206e-16 1.917977e-14     -0.3743460           34
    ## PTEN.5728   0.000000e+00 0.0000000000                  4.211950           4.49610                  4.748700 2.804993e-23 1.690008e-21     -0.4442587           24
    ## TP53.7157   0.000000e+00 0.0000000000                  5.190550           5.65895                  6.052850 7.916889e-10 3.193411e-08     -0.2878403          261
    ## NOTCH1.4851 2.785176e-05 0.0005152575                  5.065250           5.64145                  6.078500 9.999999e-01 1.000000e+00      0.2156026           44

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