IntOGen Plus | Oncodrive3D v0.1 + LHS combination

Running TCGA + HARTWIG it returns two uncompleted Combination for two cohorts:

HARTWIG_WGS_MCC_2020 Expected v2023 results
HARTWIG_WGS_THYM_2020 Unexpected v2023 results

THYM ttype

There are two cohorts in intogen 2023 for this ttype:

HARTWIG_WGS_THYM_2020 - samples 11
TCGA_WXS_THYM- samples 122

For the failing cohort there are 3 genes that are detected as drivers in the v2023 which are SMARCA4, KIT and FAM135B, for

Only SMARCA4 is detected in the TCGA cohort, KIT and FAM135B are unique to the HARTWIGone.

The main difference between the two runs is the following:

run 2023 Grid optimization run on 4 methods:

dict_keys(['oncodrivefml', 'oncodriveclustl', 'dndscv', 'smregions', 'cbase', 'hotmaps'])
[QC] {'smregions', 'oncodriveclustl', 'mutpanning'} discarded
Running on ['oncodrivefml', 'dndscv', 'cbase', 'hotmaps']
Optimization terminated successfully    (Exit mode 0)
            Current function value: -2.6676666909499587
            Iterations: 3
            Function evaluations: 28
            Gradient evaluations: 3
Iteration limit reached    (Exit mode 9)
            Current function value: -2.6676666909499587
            Iterations: 25
            Function evaluations: 440
            Gradient evaluations: 25
{'oncodrivefml': 0.25, 'oncodriveclustl': 0.0, 'dndscv': 0.25, 'smregions': 0.0, 'cbase': 0.25, 'hotmaps': 0.25}

run o3d + normal combination

[QC] {'seismic', 'oncodriveclustl', 'mutpanning', 'smregions', 'oncodrive3d'} discarded
Running on ['oncodrivefml', 'dndscv', 'cbase']
{'oncodrivefml': None, 'oncodriveclustl': None, 'dndscv': None, 'smregions': None, 'cbase': None, 'oncodrive3d': None}
Singular matrix E in LSQ subproblem    (Exit mode 5)
            Current function value: -2.1844151605103335
            Iterations: 1
            Function evaluations: 19
            Gradient evaluations: 2
Singular matrix E in LSQ subproblem    (Exit mode 5)
            Current function value: -2.1844151605103335
            Iterations: 1
            Function evaluations: 19
            Gradient evaluations: 2
{'oncodrivefml': None, 'oncodriveclustl': None, 'dndscv': None, 'smregions': None, 'cbase': None, 'oncodrive3d': None}

run o3d + LHS combination It never reaches an optimal solution

[QC] {'oncodriveclustl', 'seismic', 'mutpanning', 'smregions', 'oncodrive3d'} discarded
Running on ['dndscv', 'oncodrivefml', 'cbase']
Singular matrix E in LSQ subproblem    (Exit mode 5)
            Current function value: -1.6014802704758488
            Iterations: 1
            Function evaluations: 19
            Gradient evaluations: 2
Singular matrix E in LSQ subproblem    (Exit mode 5)
            Current function value: -1.6014802704758488
            Iterations: 1
            Function evaluations: 19
            Gradient evaluations: 2
{'dndscv': nan, 'oncodrivefml': nan, 'oncodriveclustl': nan, 'smregions': nan, 'cbase': nan, 'oncodrive3d': nan}

Important NOTE:

CBaSE fix could play an important role in this case because in the v2023 run it was bugged and every gene was return as a hit. In the new run this does not happen:

❯ zcat ../v2023/20230224_release2023/run/work/7c/6cc8e3ada748749d1661ff1f717310/HARTWIG_WGS_THYM_2020.cbase.tsv.gz| head
gene    p_pos   q_pos   mis_obs non_obs syn_obs
A1BG    1.428265e-02    1.428265e-02    0   0   0
A1CF    1.428265e-02    1.428265e-02    0   0   0
A2M 1.428265e-02    1.428265e-02    0   0   0
A2ML1   1.428265e-02    1.428265e-02    0   0   0
A3GALT2 1.428265e-02    1.428265e-02    0   0   0
A4GALT  1.428265e-02    1.428265e-02    0   0   0
A4GNT   1.428265e-02    1.428265e-02    0   0   0
AAAS    1.428265e-02    1.428265e-02    0   0   0
AACS    1.428265e-02    1.428265e-02    0   0   0
❯ zcat work/cb/2a93aa0134864c3b2fd129e5f62077/HARTWIG_WGS_THYM_2020.cbase.tsv.gz| head
gene    p_pos   q_pos   mis_obs non_obs syn_obs
A1BG    1.000000e+00    1.000000e+00    0   0   0
A1CF    1.000000e+00    1.000000e+00    0   0   0
A2M 1.000000e+00    1.000000e+00    0   0   0
A2ML1   1.000000e+00    1.000000e+00    0   0   0
A3GALT2 1.000000e+00    1.000000e+00    0   0   0
A4GALT  1.000000e+00    1.000000e+00    0   0   0
A4GNT   1.000000e+00    1.000000e+00    0   0   0
AAAS    1.000000e+00    1.000000e+00    0   0   0
AACS    1.000000e+00    1.000000e+00    0   0   0

bbglab / intogen-plus

IntOGen Plus | Oncodrive3D v0.1 + LHS combination #12

THYM ttype

Important NOTE: