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TCGA Workflow: Analyze cancer genomics and epigenomics data using Bioconductor packages (workflow package) #229

Closed tiagochst closed 7 years ago

tiagochst commented 7 years ago

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bioc-issue-bot commented 7 years ago

Hi @tiagochst

Thanks for submitting your package. We are taking a quick look at it and you will hear back from us soon.

The DESCRIPTION file for this package is:

Package: f1000_TCGA_Workflow
Title: TCGA Workflow  Analyze cancer genomics and epigenomics data using Bioconductor packages
Version: 0.99.0
Date: 2016-12-28
Author: 
  Tiago Chedraoui Silva  <tiagochst@usp.br>,
  Antonio Colaprico <antonio.colaprico@ulb.ac.be>,
  Catharina Olsen <colsen@ulb.ac.be>,
  Fulvio D Angelo <fulvio.dan13@gmail.com>,
  Gianluca Bontempi <gbonte@ulb.ac.be>,
  Michele Ceccarelli <m.ceccarelli@gmail.com>,
  Houtan Noushmehr <houtan@usp.br>
Maintainer: Tiago Chedraoui Silva <tiagochst@usp.br>
Description: A workflow pacakge to analyze cancer genomics and epigenomics data using Bioconductor packages
Depends: 
  R (>= 3.3.0), 
  downloader (>= 0.4),
  TCGAbiolinks,
  stringr,
  SummarizedExperiment,
  ELMER,
  gaia,
  parallel,
  ChIPseeker,
  ComplexHeatmap,
  clusterProfiler,
  minet,
  c3net,
  biomaRt,
  pathview,
  BSgenome.Hsapiens.UCSC.hg19,
  MotifDb,
  MotIV,
  rGADEM,
  motifStack,
  circlize,
  c3net,
  pbapply,
  gplots,
  ChIPseeker,
  pbapply,
  GenomeInfoDb,
  ggplot2,
  AnnotationHub
License: GPL (>= 3)
VignetteBuilder: knitr
biocViews: WorkflowStep
Suggests: knitr, knitcitations
NeedsCompilation: no
URL: https://f1000research.com/articles/5-1542/v2
BugReports: https://github.com/BioinformaticsFMRP/f1000_TCGA_Workflow/issues
bioc-issue-bot commented 7 years ago

Your package has been approved for building. Your package is now submitted to our queue.

IMPORTANT: Please read the instructions for setting up a push hook on your repository, or further changes to your repository will NOT trigger a new build.

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

Congratulations! The package built without errors or warnings on all platforms.

Please see the following build report for more details:

http://bioconductor.org/spb_reports/f1000_TCGA_Workflow_buildreport_20161230151028.html

vobencha commented 7 years ago

Hi,

The Depends field in DESCRIPTION should list the packages from which you call functions or create classes. Looks like it might boil down to just these library(TCGAbiolinks) library(stringr) library(ComplexHeatmap) library(SummarizedExperiment

The rest can go in Suggests. Please add a NAMESPACE to import the packages in Depends.

Valerie

bioc-issue-bot commented 7 years ago

We only start builds when the Version field in the DESCRIPTION file is incremented. For example, by changing

Version: 0.99.0

to

Version 0.99.1

If you did not intend to start a build, you don't need to do anything. If you did want to start a build, increment the Version: field and try again.

bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

b9270e6 version bump

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

Congratulations! The package built without errors or warnings on all platforms.

Please see the following build report for more details:

http://bioconductor.org/spb_reports/f1000_TCGA_Workflow_buildreport_20170109172238.html

bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

250a138 Fixes

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

Congratulations! The package built without errors or warnings on all platforms.

Please see the following build report for more details:

http://bioconductor.org/spb_reports/f1000_TCGA_Workflow_buildreport_20170109172642.html

bioc-issue-bot commented 7 years ago

We only start builds when the Version field in the DESCRIPTION file is incremented. For example, by changing

Version: 0.99.0

to

Version 0.99.1

If you did not intend to start a build, you don't need to do anything. If you did want to start a build, increment the Version: field and try again.

tiagochst commented 7 years ago

@vobencha Hi, thank you for the review, I added the namespace. I'm sorry if I understood it wrong, but all the Depends have at least one function being used. I added those functions to the package NAMESPACE.

bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

cb3d0fe Version bump

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

Congratulations! The package built without errors or warnings on all platforms.

Please see the following build report for more details:

http://bioconductor.org/spb_reports/f1000_TCGA_Workflow_buildreport_20170109173225.html

vobencha commented 7 years ago

OK, slight change of plans. These 'workflows as packages' are still somewhat new so we are figuring the process out. Since you don't have any internal R code the packages are only needed for the vignette. Please move the list of packages to 'Suggests' and don't import them in the NAMESPACE. You should still have a NAMESPACE but for now it will be empty.

Thanks. Valerie

bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

78cf21f Moving list of packages to 'Suggests' and dont imp...

tiagochst commented 7 years ago

Hi Valerie,

It is done.

Best regards, Tiago

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

Congratulations! The package built without errors or warnings on all platforms.

Please see the following build report for more details:

http://bioconductor.org/spb_reports/f1000_TCGA_Workflow_buildreport_20170111191004.html

vobencha commented 7 years ago

Please see comments and suggestions below.

1) R/ vs vignette/ directory

A workflow package usually doesn't define new R functions but reuses from existing packages. Defining little functions used in *apply() loops are fine but the vignette is not the place to define substantial helpers. If you need substantial helper functions they should be in R/, not the vignette. Please move the functions from the "internal functions" section in the vignette to R/utilities.R. Also add a man page, man/utilities.Rd, that briefly documents them and export them in the NAMESPACE. The functions they depend on will need to be moved from Suggests to Depends or Imports and import() or importFrom() in the NAMESPACE.

I think all of these should be moved to utilities.R:

~/proj/git/software/f1000_TCGA_Workflow/vignettes >grep "<- function" * f1000.Rmd:matched_met_exp <- function(project, n = NULL){ f1000.Rmd:gaiaCNVplot <- function (calls, cancer=NULL, threshold=0.01) f1000.Rmd:gaiaCNVplot <- function (calls, cancer=NULL, threshold=0.01) f1000.Rmd:get.adjacency.biogrid <- function(tmp.biogrid, names.genes = NULL){ f1000.Rmd:matched_met_exp <- function(project, n = NULL){ f1000.Rmd:matched_met_exp <- function(project, n = NULL){ f1000.Rmd:TCGAsurvival_TFplot <- function(TF,mee, clinical, percentage = 0.3){ f1000.Rmd:TCGAsurvival_TFplot <- function(TF,mee, clinical, percentage = 0.3){

Sorry for missing this on the first review but the extra code really clutters the vignette and should be split out.

2) R CMD build

I cannot build the package:

~/proj/git/software >R-dev CMD build f1000_TCGA_Workflow/
* checking for file ‘f1000_TCGA_Workflow/DESCRIPTION’ ... OK
* preparing ‘TCGAWorkflow’:
* checking DESCRIPTION meta-information ... OK
* installing the package to build vignettes
* creating vignettes ... ERROR
See system.file("LICENSE", package="MotifDb") for use restrictions.
Download DNA methylation information
Accessing GDC. This might take a while...
Download gene expression information
Accessing GDC. This might take a while...
Download DNA methylation information
Accessing GDC. This might take a while...
Download gene expression information
Accessing GDC. This might take a while...
Accessing GDC. This might take a while...
GDCdownload will download 10 files. A total of 212.858413 MB
Downloading as: Thu_Jan_12_06_28_07_2017.tar.gz
Downloading genome information. Using: Homo sapiens genes (GRCh37.p13)
Quitting from lines 54-235 (f1000.Rmd)
Error: processing vignette 'f1000.Rmd' failed with diagnostics:
Request to BioMart web service failed. Verify if you are still connected to the internet.  Alternatively the BioMart web service is temporarily down.
Execution halted

The calls to BioMart (or any web service) must be wrapped in tryCatch() and given a limited number of tries. Please look at the GEOsearch/R/utilities.R file. Martin recently helped that author design functions that read / access urls with a timeout. Such precautions can prevent the package from putting unnecessary load on the build machines. These also flag web sites that are unreliable. Please wrap your download calls in similar helper functions. If after 3 tries you can't get the file, either error out or move forward in the workflow without that data.

3) loading packages

Load each package once. If they are loaded at the top of the vignette they do not need to be loaded again in separate sections. For example, this is the number of times the TCGAbiolinks package is loaded:

~/f1000_TCGA_Workflow/vignettes >grep "library(TCGAbiolinks)" * f1000.Rmd: library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks)

4) Direct slot access Accessing class slots with '@' goes against best practices. There are many reasons for this - slot names can change, the class can be invalidated if the wrong data is put in the slot etc. Instead you should use getter and setters to access and change the data. Do these classes not have accessor functions? Please explain why you are using '@' throughout the code.

Please do NOT encourage the user to use '@':

# To access the data you should use the getData function
# or simply access with @ (for example gbm.data@Clinical)
gbm.mut <- getData(gbm.data,"Mutations")
gbm.clin <- getData(gbm.data,"Clinical")
gbm.gistic <- getData(gbm.data,"GISTIC")

Does this class not have accessors?

# get GISTIC results
gistic.allbygene <- gistic@GISTIC@AllByGene
gistic.thresholedbygene <- gistic@GISTIC@ThresholedByGene

5) I would reword this to say the workflow 'makes use' of these packages, not 'introduces' them.

This workflow introduces the following Bioconductor packages:

* [AnnotationHub](http://www.bioconductor.org/packages/AnnotationHub/)
* [ChIPSeeker](http://www.bioconductor.org/packages/ChIPseeker/)
* [ComplexHeatmap](http://www.bioconductor.org/packages/ComplexHeatmap/)
* [pathview](http://www.bioconductor.org/packages/pathview/)
* [ELMER](http://www.bioconductor.org/packages/ELMER/)
* [GAIA](http://www.bioconductor.org/packages/gaia/)
* [MINET](http://www.bioconductor.org/packages/minet/)
* [RTCGAtoolbox](http://www.bioconductor.org/packages/RTCGAtoolbox/)
* [TCGAbiolinks](http://www.bioconductor.org/packages/TCGAbiolinks/)
* [AnnotationHub](http://www.bioconductor.org/packages/GAIA/)

Also, this is not a complete list of packages used in the vignette. It will be difficult to keep this up to date. I would suggest removing this section and just cite or talk about the packages as you go along in the vignette. Alternatively, you could mention once, at the top of the vignette that package landing pages can be found through the biocViews interface here:

http://www.bioconductor.org/packages/release/BiocViews.html#___Software

Valerie

tiagochst commented 7 years ago

Thank you for the review. I'll work on those points next week. I'll let you know when I fix them.

Tiago Chedraoui Silva

On Thu, Jan 12, 2017 at 8:48 AM, vobencha notifications@github.com wrote:

Please see comments and suggestions below.

  1. R/ vs vignette/ directory

A workflow package usually doesn't define new R functions but reuses from existing packages. Defining little functions used in *apply() loops are fine but the vignette is not the place to define substantial helpers. If you need substantial helper functions they should be in R/, not the vignette. Please move the functions from the "internal functions" section in the vignette to R/utilities.R. Also add a man page, man/utilities.Rd, that briefly documents them and export them in the NAMESPACE. The functions they depend on will need to be moved from Suggests to Depends or Imports and import() or importFrom() in the NAMESPACE.

I think all of these should be moved to utilities.R:

~/proj/git/software/f1000_TCGA_Workflow/vignettes >grep "<- function" * f1000.Rmd:matched_met_exp <- function(project, n = NULL){ f1000.Rmd:gaiaCNVplot <- function (calls, cancer=NULL, threshold=0.01) f1000.Rmd:gaiaCNVplot <- function (calls, cancer=NULL, threshold=0.01) f1000.Rmd:get.adjacency.biogrid <- function(tmp.biogrid, names.genes = NULL){ f1000.Rmd:matched_met_exp <- function(project, n = NULL){ f1000.Rmd:matched_met_exp <- function(project, n = NULL){ f1000.Rmd:TCGAsurvival_TFplot <- function(TF,mee, clinical, percentage = 0.3){ f1000.Rmd:TCGAsurvival_TFplot <- function(TF,mee, clinical, percentage = 0.3){

Sorry for missing this on the first review but the extra code really clutters the vignette and should be split out.

  1. R CMD build

I cannot build the package:

~/proj/git/software >R-dev CMD build f1000_TCGA_Workflow/

  • checking for file ‘f1000_TCGA_Workflow/DESCRIPTION’ ... OK
  • preparing ‘TCGAWorkflow’:
  • checking DESCRIPTION meta-information ... OK
  • installing the package to build vignettes
  • creating vignettes ... ERROR See system.file("LICENSE", package="MotifDb") for use restrictions. Download DNA methylation information Accessing GDC. This might take a while... Download gene expression information Accessing GDC. This might take a while... Download DNA methylation information Accessing GDC. This might take a while... Download gene expression information Accessing GDC. This might take a while... Accessing GDC. This might take a while... GDCdownload will download 10 files. A total of 212.858413 MB Downloading as: Thu_Jan_12_06_28_07_2017.tar.gz Downloading genome information. Using: Homo sapiens genes (GRCh37.p13) Quitting from lines 54-235 (f1000.Rmd) Error: processing vignette 'f1000.Rmd' failed with diagnostics: Request to BioMart web service failed. Verify if you are still connected to the internet. Alternatively the BioMart web service is temporarily down. Execution halted

The calls to BioMart (or any web service) must be wrapped in tryCatch() and given a limited number of tries. Please look at the GEOsearch/R/utilities.R file. Martin recently helped that author design functions that read / access urls with a timeout. Such precautions can prevent the package from putting unnecessary load on the build machines. These also flag web sites that are unreliable. Please wrap your download calls in similar helper functions. If after 3 tries you can't get the file, either error out or move forward in the workflow without that data.

  1. loading packages

Load each package once. If they are loaded at the top of the vignette they do not need to be loaded again in separate sections. For example, this is the number of times the TCGAbiolinks package is loaded:

~/f1000_TCGA_Workflow/vignettes >grep "library(TCGAbiolinks)" * f1000.Rmd: library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks) f1000.Rmd:library(TCGAbiolinks)

  1. Direct slot access Accessing class slots with '@' goes against best practices. There are many reasons for this - slot names can change, the class can be invalidated if the wrong data is put in the slot etc. Instead you should use getter and setters to access and change the data. Do these classes not have accessor functions? Please explain why you are using '@' throughout the code.

Please do NOT encourage the user to use '@':

To access the data you should use the getData function

or simply access with @ (for example gbm.data@Clinical)

gbm.mut <- getData(gbm.data,"Mutations") gbm.clin <- getData(gbm.data,"Clinical") gbm.gistic <- getData(gbm.data,"GISTIC")

Does this class not have accessors?

get GISTIC results

gistic.allbygene <- gistic@GISTIC@AllByGene gistic.thresholedbygene <- gistic@GISTIC@ThresholedByGene

  1. I would reword this to say the workflow 'makes use' of these packages, not 'introduces' them.

This workflow introduces the following Bioconductor packages:

Also, this is not a complete list of packages used in the vignette. It will be difficult to keep this up to date. I would suggest removing this section and just cite or talk about the packages as you go along in the vignette. Alternatively, you could mention once, at the top of the vignette that package landing pages can be found through the biocViews interface here:

http://www.bioconductor.org/packages/release/BiocViews.html#___Software

Valerie

— You are receiving this because you were mentioned. Reply to this email directly, view it on GitHub https://github.com/Bioconductor/Contributions/issues/229#issuecomment-272216240, or mute the thread https://github.com/notifications/unsubscribe-auth/AAI4eb9j9GvQZVDCcmZiMVSWdJs5nD1Gks5rRll6gaJpZM4LXEEt .

bioc-issue-bot commented 7 years ago

We only start builds when the Version field in the DESCRIPTION file is incremented. For example, by changing

Version: 0.99.0

to

Version 0.99.1

If you did not intend to start a build, you don't need to do anything. If you did want to start a build, increment the Version: field and try again.

bioc-issue-bot commented 7 years ago

We only start builds when the Version field in the DESCRIPTION file is incremented. For example, by changing

Version: 0.99.0

to

Version 0.99.1

If you did not intend to start a build, you don't need to do anything. If you did want to start a build, increment the Version: field and try again.

bioc-issue-bot commented 7 years ago

We only start builds when the Version field in the DESCRIPTION file is incremented. For example, by changing

Version: 0.99.0

to

Version 0.99.1

If you did not intend to start a build, you don't need to do anything. If you did want to start a build, increment the Version: field and try again.

bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

03d70a6 Considering suggestion 5 e3388d3 Linking paper to workflow 4611a92 Finishing changes requested from vobencha

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

Congratulations! The package built without errors or warnings on all platforms.

Please see the following build report for more details:

http://bioconductor.org/spb_reports/f1000_TCGA_Workflow_buildreport_20170114190643.html

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

Congratulations! The package built without errors or warnings on all platforms.

Please see the following build report for more details:

http://bioconductor.org/spb_reports/f1000_TCGA_Workflow_buildreport_20170114190752.html

tiagochst commented 7 years ago

@vobencha I updated the workflow

vobencha commented 7 years ago

Hi, Thanks for making the changes. A few more comments below. The most important is the amount of data being downloaded and processed (#9).

  1. Inconsistent names The github repo is f1000_TCGA_Workflow, the title in DESCRIPTION is TCGAWorkflow and the title of the vignette is f1000.Rnw. I'd suggest making a more descriptive name for the vigentte, if nothing else have it match the title of the package, e.g., TCGAWorkflow.Rnw.

  2. export functions used in the vignette Functions defined in the R/ directory will need to be exported for use in the vignette. Please add the exported functions to the NAMESPACE and load the package at the top of the vignette, e.g., library(TCGAWorkflow).

  3. no output from the single package builder You may have noticed this ... ? I think the package is not completing R CMD build. Have you run R CMD build and R CMD check? I tried running R CMD build and it was still running after 50 minutes.

  4. volume of downloads The show stopper is the amount of data you are trying to download a process. The vignette tries to download > 600 files totaling > 2000 MB. Here is just part of the output from running the vignette before I killed it:

    GDCdownload will download 10 files. A total of 212.965792 MB
    Downloading as: Thu_Jan_19_10_10_55_2017.tar.gz
    ...
    Of the 156 files for download 10 already exist.
    We will download only those that are missing ones.
    GDCdownload will download 146 files. A total of 221.007115 MB
    ...
    Of the 516 files for download 10 already exist.
    We will download only those that are missing ones.
    GDCdownload will download 506 files. A total of 768.699866 MB

    and the list goes on.

Unfortunately this is not reasonable (in time or space) to run on our build machines and I can't imagine it would be easy for a user to reproduce. Can you find similar data in one of the Bioconductor repos? There are quite a few TCGA data sets in the ExperimentalData repo (type 'TCGA' in search box).

http://www.bioconductor.org/packages/release/BiocViews.html#___AnnotationData http://www.bioconductor.org/packages/release/BiocViews.html#___ExperimentData

If not, you could create your own experimental data package that can be reused in the workflow package.

Valerie

tiagochst commented 7 years ago

@vobencha Hi,

What do you think about this approach, do you believe this would help the workflow to be easier ? Unfortunately, we would need to have more samples to have significant results. But I agree it should be faster.

tiagochst commented 7 years ago

By the way, when I changed the name of the repository the commit are not linked to this issue. How should I proceed to fix it? The last version is in the github repository

vobencha commented 7 years ago

I'm cc'ing @mtmorgan to help with this. Martin, how should we proceed when the repo has changed names? Initially I thought we needed to close this issue and open another but I think that may not be the case. Val

mtmorgan commented 7 years ago

I think the link in the original comment that opened the issue can be edited to point to the new repo.

tiagochst commented 7 years ago

I changed the link, but it didn't work. Should I close and open another issue?

mtmorgan commented 7 years ago

Does the new repository have the web hook defined? Can you confirm that the web hook fired on version bump -- under 'Settings' on top right of repository page, 'Web hooks', the link should appear, click on 'Edit' and scroll down to top of the hash tags; look for the one fired at the time of the version bump and 'Response' status.

tiagochst commented 7 years ago
screen shot 2017-01-25 at 11 05 42 am
mtmorgan commented 7 years ago

Thanks, this is the first time we've dealt with this; can you press the 'Redeliver' button on the Recent Delivery you show above?

bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

200e14c Only 4 notes

tiagochst commented 7 years ago

@mtmorgan @vobencha Thanks! It worked. I have to send all the lost commits?

bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

077adaa Fixing 7bd8bbf version bump

bioc-issue-bot commented 7 years ago

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bioc-issue-bot commented 7 years ago

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fbbccaa Version bump

bioc-issue-bot commented 7 years ago

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9524254 Fixing manual

bioc-issue-bot commented 7 years ago

Dear Package contributor,

This is the automated single package builder at bioconductor.org.

Your package has been built on Linux, Mac, and Windows.

On one or more platforms, the build results were: "skipped, ERROR". This may mean there is a problem with the package that you need to fix. Or it may mean that there is a problem with the build system itself.

Please see the following build report for more details:

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bioc-issue-bot commented 7 years ago

Received a valid push; starting a build. Commits are:

5b0a65c Bug fix

vobencha commented 7 years ago

Hi, Responding to comments in https://github.com/Bioconductor/Contributions/issues/229#issuecomment-274941697. Thanks for addressing many of the issues.

8. 30 minutes is a reasonable amount of time for the workflow to run.

9. I understand results are more meaningful when more data are downloaded, however, 500 MB is too much. It would be ok to show the full download in the vignette but not evaluate it and say 'instead we will download a subset ... etc.'. Clearly state the full download is >= 500 MB so users without a sufficient internet connection or space are forewarned.

The data should not be included in the workflow package but should be a separate experimental data package.

Valerie

tiagochst commented 7 years ago

OK! I'll create the experimental data package. Just to know, I'll need to create another issue? How do I link the issue with this one?