Thank you David, everything is clear. I will write to the PEAKS support
team tomorrow.

Best,
Sergio

--------------------------
Sergio Ciordia Higuera
Proteomics Facility
National Center for Biotechnology
C\Darwin, 3
Universidad Autónoma de Madrid
Cantoblanco
28049 Madrid (Spain)
Phone: +34 91 585 4540 / 4695
Fax: +34 91 585 4506


El dom, 13 oct 2024 a las 5:52, David Shteynberg (<
[email protected]>) escribió:

> Hello Sergio,
>
> My answers are in bold:
>
> *- Should the file collect all the PSMs or only the peptides?.*
>
> * If we are trying to replicate  how TPP processes other search engines
> then, yes collect all PSMs without filtering and let the TPP process the
> pepXML.*
>
> *- Should the file contain the decoys? In this way, it would not be
> necessary to use the strategy of the ‘unknown decoys’ or yes?*
>
> *The results should contains the ‘unknown decoys’, any ‘known decoys’ that
> are exposed to the search engine are no longer reliable as independent
> indicators of false positive results and should be excluded (ignored) from
> further FDR estimates.*
>
> *- They have to correct the calculated neutral masses and mass
> differences bug*
>
> *Yes!*
>
> *- Should the pepXML file be filtered by FDR?. This last point seems
> important to me because the file I gave you seems to me to be filtered by
> 1% FDR at the PSM level (you can't change it unless you repeat the search
> in PEAKS and set a less strict value). In case the pepXML file has to be
> exported with an FDR value, what should it be for the TPP analysis?*
>
> *No.  You can have all results exported from PEAKS (maximum FDR without
> filtering) and let TPP establish the thresholds for FDR.  You can then
> apply TPP based FDR thresholds without rerunning the analysis (assuming the
> minimum probability for reported PSMs is set to zero.)*
>
> Best,
> -David
>
>
> On Oct 12, 2024, at 12:41 AM, Sergio Ciordia <[email protected]> wrote:
>
> Thank you very much David for such a thorough analysis, for the effort and
> your time. I agree with you that there seems to be a bug in the pepXML
> export. I'm going to write to support to see if they can fix it (and fast).
> Since I'm going to write to them, what exactly would we need to do the
> analysis with TPP? For example:
>
> - Should the file collect all the PSMs or only the peptides?.
> - Should the file contain the decoys? In this way, it would not be
> necessary to use the strategy of the ‘unknown decoys’ or yes?.
> - They have to correct the calculated neutral masses and mass
> differences bug.
> - Should the pepXML file be filtered by FDR?. This last point seems
> important to me because the file I gave you seems to me to *be filtered
> by 1% FDR at the PSM level *(you can't change it unless you repeat the
> search in PEAKS and set a less strict value). In case the pepXML file has
> to be exported with an FDR value, what should it be for the TPP analysis?
>
> Let's see if we can get it to work. Thanks again for all your help in
> trying to implement PEAKS in TPP and all the comparative analysis with
> Comet.
>
> Best regards,
> Sergio
>
> --------------------------
> Sergio Ciordia Higuera
> Proteomics Facility
> National Center for Biotechnology
> C\Darwin, 3
> Universidad Autónoma de Madrid
> Cantoblanco
> 28049 Madrid (Spain)
> Phone: +34 91 585 4540 / 4695
> Fax: +34 91 585 4506
>
>
> El sáb, 12 oct 2024 a las 2:18, David Shteynberg (<
> [email protected]>) escribió:
>
>> Hello Sergio,
>>
>> After having a much closer look at this data I am having some doubts
>> regarding the data as it is reported in the PEAKS pepXML output.  First of
>> all I noticed that the mass differences and the calculated neutral masses
>> were off in the pepXML export, for example:
>>
>> <PastedGraphic-1.png>
>>
>> So I modified my tools to allow recomputing the calculated neutral masses
>> and mass differences.  Here is this entry after I run my tool:
>>
>> <PastedGraphic-2.png>
>>
>> Although the calculated neutral mass is now correct, the mass difference
>> for this PSM is quite large, and possibly represents another modification
>> in this peptide that is not annotated by PEAKS for this PSM.  The mass of
>> 16 Da matches oxidation and I see many of these types of peptides, with a
>> massdiff of 16 and containing a Methionine.
>>
>>
>> This leads me to suspect a bug in the pepXML export of these PSMs from
>> PEAKS.
>>
>> I was able to get quite good results running your mzML file through
>> comet.  These are the comet modifications I used in my search:
>>
>> <PastedGraphic-3.png>
>>
>> *<PastedGraphic-4.png>*
>>
>>
>> Although I am uncertain that this will fix all of the issues I am seeing
>> in this result, is it possible to rerun PEAKS using a similar set of
>> modifications, I used here for comet?
>>
>> Another concern was that out of over 26,000 PSMs in the pepXML file only
>> 48 are hits to the DECOY portion of the database.  This seems a bit low to
>> me, and I am not sure why that is.
>>
>>
>> Here is the summary from the comet + TPP analysis of this run:
>> <image.png>
>>
>> Comet + PeptideProphet is finding about 24000 correct PSMs at an
>> error-rate less than 1%.
>>
>> Running iProphet on the data boost the PSM number higher, especially at
>> the lower error-rates:
>>
>> <PastedGraphic-5.png>
>>
>>
>> To summarize, comet+PeptideProphet+iProphet is finding about 24000
>> correct PSMs, mapping to almost 21000 peptide sequences in this file:
>>
>> <PastedGraphic-6.png>
>>
>>
>> Perhaps if the PEAKS issues can be solved, a similar number can be found
>> using that software, but for now the results coming out of PEAKS are not
>> close.
>>
>> Best,
>> -David
>>
>>
>>
>>
>>
>>
>> On Oct 10, 2024, at 2:43 PM, Sergio Ciordia <[email protected]> wrote:
>>
>> Hi David,
>>
>> I have anticipated your answer and I think this is what you asked for. I
>> have used TPP to generate the DECOY database using these settings:
>>
>> <image.png>
>>
>> I have searched PEAKS again and uploaded the new file ‘
>> PEAKS_target_decoy.pep.xml’ and the decoy database to the shared folder.
>>
>> Link: PEAKS Dataset
>> <https://drive.google.com/drive/folders/1Q3LF1wRTM62KfS20dfXmToQMY9ji9Dug>
>>
>> See what you think of the output.
>>
>> Best,
>> Sergio
>>
>> --------------------------
>> Sergio Ciordia Higuera
>> Proteomics Facility
>> National Center for Biotechnology
>> C\Darwin, 3
>> Universidad Autónoma de Madrid
>> Cantoblanco
>> 28049 Madrid (Spain)
>> Phone: +34 91 585 4540 / 4695
>> Fax: +34 91 585 4506
>>
>>
>> El jue, 10 oct 2024 a las 22:47, Sergio Ciordia (<[email protected]>)
>> escribió:
>>
>>> OK, I think I understand you now. I think what you are asking me to do
>>> is to create a database containing the target and decoy entries and repeat
>>> the search. Then in the output that PEAKS gives us, we could locate the
>>> ‘unknown’ decoy. Is this what you need?.
>>>
>>> Sergio
>>>
>>> --------------------------
>>> Sergio Ciordia Higuera
>>> Proteomics Facility
>>> National Center for Biotechnology
>>> C\Darwin, 3
>>> Universidad Autónoma de Madrid
>>> Cantoblanco
>>> 28049 Madrid (Spain)
>>> Phone: +34 91 585 4540 / 4695
>>> Fax: +34 91 585 4506
>>>
>>>
>>> El jue, 10 oct 2024 a las 22:33, 'David Shteynberg' via spctools-discuss
>>> (<[email protected]>) escribió:
>>>
>>>> I think we have a bit of misunderstanding here.  I am not looking for
>>>> decoys that are "known" to PEAKS,  I want to include entrapment decoys that
>>>> are "unknown" to PEAKS and known to us as true negatives.  Then we can
>>>> utilized the true negatives to estimate error rates.  The true negative
>>>> entrapment decoys should not be revealed to the search algorithm, just like
>>>> the false positives among the target sequences are not known to the
>>>> algorithm, but represent the error we are trying to control.
>>>>
>>>> I hope this makes sense.
>>>>
>>>> -David
>>>>
>>>> On Thu, Oct 10, 2024 at 10:48 AM Sergio Ciordia <[email protected]>
>>>> wrote:
>>>>
>>>>> Hi David,
>>>>>
>>>>> There are several commercial softwares such as PEAKS or Proteome
>>>>> Discoverer that you upload the target database directly and they 
>>>>> internally
>>>>> generate the Target-Decoy database. The problem is that when you launch 
>>>>> the
>>>>> search and get the output, the software usually removes the decoy entries
>>>>> from the final results and that's why they don't appear in the list.
>>>>>
>>>>> I understand then that we would need the same ‘pep.xml’ file but
>>>>> containing all the target and decoy entries. Is that what you need?.
>>>>>
>>>>> Best,
>>>>> Sergio
>>>>>
>>>>> --------------------------
>>>>> Sergio Ciordia Higuera
>>>>> Proteomics Facility
>>>>> National Center for Biotechnology
>>>>> C\Darwin, 3
>>>>> Universidad Autónoma de Madrid
>>>>> Cantoblanco
>>>>> 28049 Madrid (Spain)
>>>>> Phone: +34 91 585 4540 / 4695
>>>>> Fax: +34 91 585 4506
>>>>>
>>>>>
>>>>> El jue, 10 oct 2024 a las 19:40, 'David Shteynberg' via
>>>>> spctools-discuss (<[email protected]>) escribió:
>>>>>
>>>>>> Hello Sergio,
>>>>>>
>>>>>> Thanks for sending this. After taking a look I have another request.
>>>>>> The database you searched against seems to not contain any entrapment
>>>>>> DECOYS to help independently validate any computed scores or
>>>>>> probabilities.  Are you able to search this data against a database
>>>>>> containing some decoys?  You can use the TPP decoy generator to create
>>>>>> decoys (we have been using deBruijn randomized sequences), or should I
>>>>>> create it and give you the database to search?
>>>>>>
>>>>>> Best,
>>>>>> -David
>>>>>>
>>>>>> On Thu, Oct 10, 2024 at 3:52 AM Sergio Ciordia <[email protected]>
>>>>>> wrote:
>>>>>>
>>>>>>> Thank you David. You are right, I attach in this new link the 3
>>>>>>> files you need: mzML, fasta and pep.xml.
>>>>>>>
>>>>>>> Link: PEAKS Dataset
>>>>>>> <https://drive.google.com/drive/folders/1Q3LF1wRTM62KfS20dfXmToQMY9ji9Dug>
>>>>>>>
>>>>>>> I hope you can do something. Thanks anyway for your concern.
>>>>>>>
>>>>>>> Best regards,
>>>>>>> Sergio
>>>>>>>
>>>>>>> --------------------------
>>>>>>> Sergio Ciordia Higuera
>>>>>>> Proteomics Facility
>>>>>>> National Center for Biotechnology
>>>>>>> C\Darwin, 3
>>>>>>> Universidad Autónoma de Madrid
>>>>>>> Cantoblanco
>>>>>>> 28049 Madrid (Spain)
>>>>>>> Phone: +34 91 585 4540 / 4695
>>>>>>> Fax: +34 91 585 4506
>>>>>>>
>>>>>>>
>>>>>>> El jue, 10 oct 2024 a las 1:34, David Shteynberg (<
>>>>>>> [email protected]>) escribió:
>>>>>>>
>>>>>>>> Thank you Sergio!  Would you mind also sending the mzML data and
>>>>>>>> the sequence database that goes along with these search results from 
>>>>>>>> PEAKS?
>>>>>>>>
>>>>>>>> Best,
>>>>>>>> -David
>>>>>>>>
>>>>>>>> On Oct 9, 2024, at 3:58 PM, Sergio Ciordia <[email protected]>
>>>>>>>> wrote:
>>>>>>>>
>>>>>>>> Hi David,
>>>>>>>>
>>>>>>>> Thank you for your quick and honest response. I am sorry to hear
>>>>>>>> that you have no funds to continue TPP implementation. I hope this 
>>>>>>>> problem
>>>>>>>> will be solved.
>>>>>>>> Nevertheless, I appreciate your consideration of evaluating a
>>>>>>>> sample file. This file contains what the PEAKS team calls ‘Peptide 
>>>>>>>> output
>>>>>>>> in pepxml’. I hope it is adequate but in any case I don't think there 
>>>>>>>> will
>>>>>>>> be a problem in getting a suitable data output for TPP if necessary. 
>>>>>>>> The
>>>>>>>> other format that can be obtained is mzidentML in case it is of 
>>>>>>>> interest.
>>>>>>>>
>>>>>>>> LINK: pepXML PEAKS sample
>>>>>>>> <https://drive.google.com/file/d/185t5m7vJPLQAj8vVpcviX_p58DHZfyAB/view?usp=sharing>
>>>>>>>>
>>>>>>>> Thanks again for your reply.
>>>>>>>>
>>>>>>>> Best regards,
>>>>>>>> Sergio
>>>>>>>>
>>>>>>>> --------------------------
>>>>>>>> Sergio Ciordia Higuera
>>>>>>>> Proteomics Facility
>>>>>>>> National Center for Biotechnology
>>>>>>>> C\Darwin, 3
>>>>>>>> Universidad Autónoma de Madrid
>>>>>>>> Cantoblanco
>>>>>>>> 28049 Madrid (Spain)
>>>>>>>> Phone: +34 91 585 4540 / 4695
>>>>>>>> Fax: +34 91 585 4506
>>>>>>>>
>>>>>>>>
>>>>>>>> El jue, 10 oct 2024 a las 0:46, David Shteynberg (<
>>>>>>>> [email protected]>) escribió:
>>>>>>>>
>>>>>>>>> Hello Sergio,
>>>>>>>>>
>>>>>>>>> Thank you for your email.  As you know PEAKS is not a search
>>>>>>>>> engine that we have integrated in the TPP, mainly because we have not 
>>>>>>>>> had
>>>>>>>>> any requests for this feature before your email.  It is something 
>>>>>>>>> that can
>>>>>>>>> be done with a bit of work and testing, but unfortunately there is
>>>>>>>>> currently no funding for us to continue this work.  I wish I had a 
>>>>>>>>> more
>>>>>>>>> satisfying answer to give you, but perhaps, if you can forward your 
>>>>>>>>> sample
>>>>>>>>> pep.xml file, we can do this if more funding becomes available.
>>>>>>>>>
>>>>>>>>> Best,
>>>>>>>>> -David
>>>>>>>>>
>>>>>>>>> On Oct 9, 2024, at 3:35 PM, Sergio Ciordia <[email protected]>
>>>>>>>>> wrote:
>>>>>>>>>
>>>>>>>>> Hi,
>>>>>>>>>
>>>>>>>>> I have been using TPP for some time now mainly to validate with
>>>>>>>>> PeptideProphet the results I get with various search engines and to
>>>>>>>>> generate a spectral library that I use in various programs. The thing 
>>>>>>>>> is
>>>>>>>>> that in my lab we are now using PEAKS (v12) and the output is really 
>>>>>>>>> good.
>>>>>>>>> I was wondering if it would be possible to include in TPP an analysis
>>>>>>>>> pipeline of the PEAKS data from the pep.xml file generated by the 
>>>>>>>>> program.
>>>>>>>>> I know it is a commercial software but the output is very good and
>>>>>>>>> I would be very grateful if you could consider including it like 
>>>>>>>>> Sequest or
>>>>>>>>> Mascot. I think it would not be complicated since they already have 
>>>>>>>>> the
>>>>>>>>> pep.xml output, it would only have to be compatible with XInteract to 
>>>>>>>>> be
>>>>>>>>> able to validate peptide-spectrum matches.
>>>>>>>>>
>>>>>>>>> If necessary I can provide a sample pep.xml file.
>>>>>>>>>
>>>>>>>>> Thank you very much.
>>>>>>>>>
>>>>>>>>> Best regards,
>>>>>>>>> Sergio
>>>>>>>>>
>>>>>>>>> --
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>>>>>>>>> .
>>>>>>>>>
>>>>>>>>>
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>>>>>>>> .
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