Hello,
First of all, thank you very much for the development of Exomiser. I have been using the tool for several months now and it has been extremely useful. However, while working with it, I have encountered some difficulties understanding certain aspects of the final prioritization results.
Before opening this issue, I carefully read the official documentation (including the development version), several GitHub issues, configuration examples, and some of the Exomiser-related publications describing its different modules and scoring strategies.
For context, I am using Exomiser on single-patient analyses only:
one VCF file
one Phenopacket
no PED file
no family segregation analysis
Even after reading the documentation, I still have several questions that I hope you may help clarify.
- How is the inheritance mode (AD/AR/etc.) determined?
I do not fully understand how Exomiser determines whether a variant is evaluated under an autosomal dominant (AD) or autosomal recessive (AR) model.
In some cases this is understandable because the variant is associated with a known disease already annotated with a specific inheritance pattern. However, how is this handled when there is no disease association available?
- Role of inheritance mode in the final Exomiser score
From the publications and documentation, I understand that the final Exomiser score is obtained through a logistic combination of:
phenotype score
variant score
However, I would like to confirm whether the Mode Of Inheritance (MOI) itself contributes directly to the final Exomiser score, or whether it is only used as a filtering/grouping mechanism before the final scoring step.
In other words:
does the MOI influence the score mathematically?
or does it only determine which variants are considered compatible candidates?
- Questions regarding inheritanceModes configuration
In the default configuration, the following section appears:
inheritanceModes:
AUTOSOMAL_RECESSIVE_COMP_HET: 2.0
MITOCHONDRIAL: 0.2
AUTOSOMAL_RECESSIVE_HOM_ALT: 0.1
X_DOMINANT: 0.1
AUTOSOMAL_DOMINANT: 0.1
X_RECESSIVE_COMP_HET: 2.0
X_RECESSIVE_HOM_ALT: 0.1
Along with these comments:
\ In cases where you do not want any cut-offs applied an empty map should be used e.g. inheritanceModes: {}
\ These are the default settings, with values representing the maximum minor allele frequency in percent (%) permitted for an
\ allele to be considered as a causative candidate under that mode of inheritance.
\ If you just want to analyse a sample under a single inheritance mode, delete/comment-out the others.
\ For AUTOSOMAL_RECESSIVE or X_RECESSIVE ensure both relevant HOM_ALT and COMP_HET modes are present.
What I do not fully understand is the following.
My current interpretation is that inheritanceModes mainly defines MAF thresholds for each inheritance model rather than enabling/disabling inheritance analysis itself.
However:
what happens if all inheritance modes are commented out?
what happens if inheritanceModes: {} is used?
Does this mean:
no inheritance filtering is applied at all?
all inheritance models remain active but without MAF cutoffs?
or alternatively that no variants are retained?
I ask this because the comments seem somewhat ambiguous:
on one hand, they suggest that commenting out inheritance modes disables those analyses
on the other hand, they suggest that an empty map removes cutoffs globally.
- Difference between inheritanceModes, frequencyFilter, and inheritanceFilter
I also noticed the presence of other filtering-related parameters such as:
frequencyFilter:
maxFrequency: 2.0
and:
inheritanceFilter: {}
This raises additional questions:
how does frequencyFilter.maxFrequency differ from the thresholds already defined inside inheritanceModes?
is inheritanceFilter functionally equivalent to enabling/disabling inheritance modes?
should inheritanceModes mainly be used only when a PED/family analysis is available?
I suspect I may be misunderstanding the interaction between these parameters, especially in single-sample analyses.
Thank you very much for your time and for the development of this excellent software.
And apologies if some of the questions are not perfectly formulated, I have tried to read as much documentation and previous discussion as possible before posting this issue, but I still have these remaining conceptual doubts.
Hello,
First of all, thank you very much for the development of Exomiser. I have been using the tool for several months now and it has been extremely useful. However, while working with it, I have encountered some difficulties understanding certain aspects of the final prioritization results.
Before opening this issue, I carefully read the official documentation (including the development version), several GitHub issues, configuration examples, and some of the Exomiser-related publications describing its different modules and scoring strategies.
For context, I am using Exomiser on single-patient analyses only:
one VCF file
one Phenopacket
no PED file
no family segregation analysis
Even after reading the documentation, I still have several questions that I hope you may help clarify.
I do not fully understand how Exomiser determines whether a variant is evaluated under an autosomal dominant (AD) or autosomal recessive (AR) model.
In some cases this is understandable because the variant is associated with a known disease already annotated with a specific inheritance pattern. However, how is this handled when there is no disease association available?
From the publications and documentation, I understand that the final Exomiser score is obtained through a logistic combination of:
phenotype score
variant score
However, I would like to confirm whether the Mode Of Inheritance (MOI) itself contributes directly to the final Exomiser score, or whether it is only used as a filtering/grouping mechanism before the final scoring step.
In other words:
does the MOI influence the score mathematically?
or does it only determine which variants are considered compatible candidates?
In the default configuration, the following section appears:
inheritanceModes:
AUTOSOMAL_RECESSIVE_COMP_HET: 2.0
MITOCHONDRIAL: 0.2
AUTOSOMAL_RECESSIVE_HOM_ALT: 0.1
X_DOMINANT: 0.1
AUTOSOMAL_DOMINANT: 0.1
X_RECESSIVE_COMP_HET: 2.0
X_RECESSIVE_HOM_ALT: 0.1
Along with these comments:
\ In cases where you do not want any cut-offs applied an empty map should be used e.g. inheritanceModes: {}
\ These are the default settings, with values representing the maximum minor allele frequency in percent (%) permitted for an
\ allele to be considered as a causative candidate under that mode of inheritance.
\ If you just want to analyse a sample under a single inheritance mode, delete/comment-out the others.
\ For AUTOSOMAL_RECESSIVE or X_RECESSIVE ensure both relevant HOM_ALT and COMP_HET modes are present.
What I do not fully understand is the following.
My current interpretation is that inheritanceModes mainly defines MAF thresholds for each inheritance model rather than enabling/disabling inheritance analysis itself.
However:
what happens if all inheritance modes are commented out?
what happens if inheritanceModes: {} is used?
Does this mean:
no inheritance filtering is applied at all?
all inheritance models remain active but without MAF cutoffs?
or alternatively that no variants are retained?
I ask this because the comments seem somewhat ambiguous:
on one hand, they suggest that commenting out inheritance modes disables those analyses
on the other hand, they suggest that an empty map removes cutoffs globally.
I also noticed the presence of other filtering-related parameters such as:
frequencyFilter:
maxFrequency: 2.0
and:
inheritanceFilter: {}
This raises additional questions:
how does frequencyFilter.maxFrequency differ from the thresholds already defined inside inheritanceModes?
is inheritanceFilter functionally equivalent to enabling/disabling inheritance modes?
should inheritanceModes mainly be used only when a PED/family analysis is available?
I suspect I may be misunderstanding the interaction between these parameters, especially in single-sample analyses.
Thank you very much for your time and for the development of this excellent software.
And apologies if some of the questions are not perfectly formulated, I have tried to read as much documentation and previous discussion as possible before posting this issue, but I still have these remaining conceptual doubts.