[ensembl-dev] Thoughts on Speeding up the Variant Effect Predictor

[Will McLaren]

Hi Rocky,

Thanks very much for the detailed feedback.

We are currently looking into ways to further optimise VEP run time, and we
are already considering a number of the solutions you propose, along with
some others. We'll definitely take a look at the things we haven't thought
of too.

Further comments inline below.

Regards

Will McLaren
Ensembl Variation


On 18 December 2014 at 15:51, Rocky Bernstein <rocky.bernstein at gmail.com>
wrote:
>
> Running the Variant Effect Predictor on a Human Genome VCF file (130780
> lines)  with a local Fasta cache (--offline) takes about 50 minutes on a
> quad-core Ubuntu box.
>
> I could give more details, but I don't think they are that important.
>
> In looking at how to speed this up, it looks like VEP goes through the VCF
> file,  is sorted by chromosome, and processes each
> Chromosome independently. A simple and obvious way to speed this up would
> be to do some sort of 24-way map/reduce.
> There is of course the --fork option on the variant_effect_predictor.pl program
> which is roughly the same idea, but it parallelizes only across the cores
> of a single computer rather than make use of multiple ones.
>
> To pinpoint the slowness better, I used Devel::NYTProf. For those of you
> who haven't used it recently, it now has flame graphs and it makes it very
> easy to see what's going on.
>

We regularly run Devel::NYTProf on the code, very useful it is too!


>
> The first thing that came out was a slowness in code to remove carriage
> returns and line feeds. This is in Bio::DB::Fasta ::subseq:
>
>      $data =~ s/\n//g;
>      $data =~ s/\r//g;
>
> Compiling the regexp, e.g:
>
>      my $nl = qr/\n/;
>      my $cr = qr/\r/;
>
>      sub subseq {
>          ....
>         $data =~ s/$nl//g;
>         $data =~ s/$cr//g;
>      }
>
> Speeds up the subseq method by about 15%. I can elaborate more or describe
> the other methods I tried and how they fared, if there's interest. But
> since this portion is really part of BioPerl and not Bio::EnsEMBL, I'll try
> to work up a git pull request on that repository.
>

Thanks, that would be useful. This regex came up in our NYTProf runs too.


>
> So now I come to the meat of what I have to say. I should have put this at
> the top -- I hope some of you are still with me.
>
> The NYTProf graphs seem to say that there is a *lot* of overhead in object
> lookup and type testing. I think some of this is already known as there
> already are calls to "weaken" and "new_fast" object creators. And there is
> this comment in
>  Bio::EnsEMBL::Variation::BaseTranscriptVariation:_intron_effects:
>
>
>     # this method is a major bottle neck in the effect calculation code so
>     # we cache results and use local variables instead of method calls
> where
>     # possible to speed things up - caveat bug-fixer!
>

One major avenue we will be investigating is subs such as this.

For each TranscriptVariationAllele object created (this represents the
overlap of a variant allele and a transcript), the VEP evaluates a number
of predicate statements. All predicates are evaluated for all objects,
without any filtering with prior knowledge (for example if we know a
variant falls entirely in the coding sequence there's no point checking if
it's intronic).

This should be fairly low-hanging fruit to pick, so this will probably be
one of the first optimisations to reach production code.


>
> In the few cases guided by NYTProf that I have looked at, I've been able
> to make reasonable speed ups at the expense of eliminating the tests
> and object overhead.
>
> For example, in EnsEMBL::Variation::BaseTranscriptVariation changing:
>
>
>  sub transcript {
>      my ($self, $transcript) = @_;
>      assert_ref($transcript, 'Bio::EnsEMBL::Transcript') if $transcript;
>      return $self->SUPER::feature($transcript, 'Transcript');
> }
>
> to:
>
>      sub transcript {
>          my ($self, $transcript) = @_;
>         return $self->{feature};
>
> Gives a noticeable speed up. But you may ask: if that happens, then we
> lose type safety and there is a potential for bugs?
> Here ist how to address these valid concerns.
>

Type safety is of course important, but there are places (such as this one)
where the setter is only ever called internally. Testing should find cases
where this is done incorrectly, but it may be possible to remove the
assert_ref() call here completely.


>
> First, I think there could be two sets of the Perl modules, such as for
> EnsEMBL::Variation::BaseTranscriptVariation. One set with all of the
> checks and another without that are fast.  A configuration parameter might
> specify which version to use. In development or by default, one might use
> the ones that check types.
>

I think having two sets of modules would be a bit clumsy and could lead to
inconsistencies between the two, even if more tests were added.


>
> Second and perhaps more import, there are the tests! If more need to be
> added, then let's add them. And one can always add a test to make sure the
> results of the two versions gives the same result.
>
> One last avenue of optimization that I'd like to explore is using say
> Inline::C or basically coding in C hot spots. In particular, consider
> Bio::EnsEMBL::Variation::Utils::VariationEffect::overlap which looks like
> this:
>
>          my ( $f1_start, $f1_end, $f2_start, $f2_end ) = @_;
>          return ( ($f1_end >= $f2_start) and ($f1_start <= $f2_end) );
>

Again, something we've thought of, but I'd be surprised if you saw that
much speedup from changing some simple int comparisons.

I believe there may be better ways to optimise this overlap code, but it's
not something we've got to yet.


>
> I haven't tried it on this hot spot, but this is something that might
> benefit from getting coded in C. Again the trade off for speed here is a
> dependency on compiling C. In my view anyone installing this locally or
> installing CPAN modules probably already does, but it does add complexity.
>
> Typically, this is handled in Perl by providing both versions, perhaps as
> separate modules.
>
> Thoughts or comments?
>
> Thanks,
>    rocky
>
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