Seb

A few bytes about me:

• Some time working with embedded avionics software,
  Ground/Plane Communications Airbus A320/A340/A380.
• PhD in Computer Science (Toulouse, 2009);
  distributed systems + multimedia.
• One first “real” post-doc (Olso);
  more distributed systems + software security.

Then, got really bored & disgusted of academic research,
⇒ back to software engineering:

• Software + Computational infrastructure @ Genomics Core of NYU-Bio.
• At the Hammer lab since Apr 2014.

Hammer Lab

15 People; within the Icahn Institute for Genomics and Multiscale Biology

Mission: Better software for biomedicine

• Infrastructure:
  • Maintain a Hadoop Cluster
• Tools:
  • Craft high-quality FOSS for common workloads in biomedicine
• Science:
  • Use the tools – Do science
  • Develop novel therapeutics or diagnostics
  • Improve outcomes and reduce costs

Bioinformatics Workflows

Example: Broad Institute's recommendations:

Bioinformatics Vs Software Engineering

We've all been there:

 $ bwa -h
[main] unrecognized command '-h'
 $ bwa --help
[main] unrecognized command '--help'
 $ bwa -help
[main] unrecognized command '-help'
 $ bwa help
[main] unrecognized command 'help'
 $ bwa WTF!
[main] unrecognized command 'WTF!'
 $ bwa
 
Program: bwa (alignment via Burrows-Wheeler transformation)
Version: 0.7.10-r789
Contact: Heng Li <lh3@sanger.ac.uk>

Usage:   bwa <command> [options]

Command: index         index sequences in the FASTA format
         mem           BWA-MEM algorithm
         fastmap       identify super-maximal exact matches
...

Bioinformatics Vs Software Engineering

Don't assume anything:

 $ samtools index some-non-existing-file.bam
[E::hts_open] fail to open file 'some-non-existing-file.bam'
 $ echo $?
0

Bioinformatics Vs Software Engineering

There is always more …

 $ ./somaticsniper -h
./somaticsniper: invalid option -- 'h'
Unrecognizd option '-?'.

 $ samtools -help
...
-s FLOAT integer part sets seed of random number generator [0]; rest sets
 fraction of templates to subsample [no subsampling]
...

##### ERROR MESSAGE: Lexicographically sorted human genome sequence detected in reference.
##### ERROR For safety's sake the GATK requires human contigs in karyotypic order: 1, 2, ..., 10, 11, ..., 20, 21, 22, X, Y with M either leading or trailing these contigs.

• and don't get me started on Casava and its HTML “report” …
• or The Broad Institute's licensing …

Workflow Engines

Need to run 100s of tools, make parameters vary, over 1000s of samples, and

• add new tools
• adapt to new versions
• install software
• assume anything can randomly fail for obscure reasons
• optimize infrastructure usage
• deal with other adverse conditions (firewalls, VPNs, etc.)
• make reproducible research easier

Workflow Engines

A lot of them.

• often specific to a platform (e.g. Hadoop)
• not flexible
• lots of assumptions (networks, file-systems, can make, etc.)
• custom DSLs (yet another half-baked Turing-complete language)
• no fault tolerance
• buggy

Ketrew

So, yes, a new one, with these goals:

• Embedded DSL → highly hackable workflows
• Multiple backends → extensible
• Correct & fault-tolerant
• Standalone or client-server → work around sys-admins

with a sane implementation language: OCaml.

Why OCaml?

Software kills people.
We are pathetically 40 years behind on the safety/security front.

Why OCaml?

Why care about programming languages & tools?

Why OCaml?

Scientific approach at choosing your tools:

Empirical Evidence? (1/2)

Human mistakes that made the news in Apr – Aug 2015:

• Finding many bugs in Sqlite with some basic fuzzing in 2015.
• 38 × radiation dosage.
• Boeing 787 shutdown bug, and reconfiguration back-door.
• Still a lot of BOFs in the list for Firefox 38 fixes.
• VENOM is cool because the authors of Qemu are believed to be among of the best C/C++ programmers on the planet.
• Large scale exploit of a 0-day on MacKeeper.
• Health System losing $ 6 × 10⁹ because of bad programming/configuration: cf. Bloomberg.
• OpenSSL Security Advisory where infinite loops and segmentation faults are still tagged “Moderate” …
• Deep look into a recent Flash™ vulnerability.
• At NYT, about US State Dept, unable to issue visas.

Empirical Evidence? (2/2)

• Fiat-Chrysler recalling approximately 1.4 million vehicles for a programmer error.
• Programming errors that enable someone to wirelessly kill someone else's whole family, with Jeeps (wired, NYT).
• The so-called “Stagefright” vulnerability: Android's multimedia library exposes 95% of Android devices to single-MMS-based root exploits.
• See in-depth study of the 0-day market from the Hacking Team leak.
• An embarrassing bug makes your rootkits undetectable on any Intel CPU younger than 18 years old.
• Mozilla's post on the recent vulnerability “Same origin violation and local file stealing via PDF reader” which was found through an “exploit found in the wild.”
• Retrospective: “History's Worst Software Bugs” … cool read.

Why OCaml?

OCaml is:

• mature and evolving
  → code from the 90's + GADTs + subtyping + modules
• rich and strict type system
  → express safety/security lightweight theorems
• focus on readability
• fast, portable, hackable
• future-friendly: start replacing some modules with Coq-extracted code

Ketrew

“Keep Track of Experimental Workflows”
github.com/hammerlab/ketrew

• EDSL/library to write programs that build workflows/pipelines
• A separate application, The “Engine”, orchestrates those workflows

Features

In the 2.0.0, from a couple of weeks ago:

• EDSL trying to be usable by OCaml beginners
• Client-server (HTTPS + JSON) (+ “degraded” standalone mode)
• A command-line client
• A WebUI
• LSF, PBS, YARN, nohup/setsid, or “Python” backends
  + plugin infrastructure to add backends

Tested with big bioinformatics pipelines, but also running backups, building documentation …

Read-only Live Demo:
ketrew-demo.mondet.org:8080/gui?filter=%28all%29&token=demotoken

Defining Workflows

let make_backup ?(gpg=true) ?(dest_base="/tmp/backup") ~host ~dir () =
  let destination ext = file ~host (sprintf "%s.%s" dest_base ext) in
  let targz = destination "tar.gz" in
  let make_targz =
    target ~done_when:targz#exists "make-tar.gz"
      ~make:(daemonize ~host
               Program.(
                 shf "cd %s/../" dir
                 && shf  "tar cfz '%s' '%s'" targz#path (Filename.basename dir))) in
  let md5 = destination "md5" in
  let md5_targz =
    target ~done_when:md5#exists "md5-of-targz" ~depends_on:[make_targz]
      ~make:(daemonize ~host Program.(shf "md5sum '%s' > '%s'" targz#path md5#path)) in
  let gpg_targets () =
    let gpg = destination "tar.gz.gpg" in
    let make_it =
      target "gpg-of-targz" ~done_when:gpg#exists ~depends_on:[make_targz; md5_targz]
        ~make:(daemonize ~host Program.(
             sh ". ~/.backup_passphrase"
             && shf "gpg -c --passphrase $BACKUP_PASSPHRASE -o '%s' '%s'"
                     gpg#path targz#path)) in
    let clean_up =
      target "rm-tar.gz" ~depends_on:[make_it]
        ~make:(daemonize ~host (Program.shf "rm -f '%s'" targz#path )) in
    [make_it; clean_up] in
  let common_ancestor =
    let depends_on = if gpg then gpg_targets () else [make_targz; md5_targz] in
    target "make-targz common ancestor" ~depends_on in
  Ketrew.Client.submit common_ancestor

Js_of_ocaml, Reactive Typed HTML5

And 3.5 MB GIFs …

Biokepi

Reusable bioinformatics pipelines using Ketrew.

• re-use intermediate results, make everything restartable
• encode knowledge about insane biology software
• give semantics to parameters, add constraints
• take care of most software installations
• improve performance, “scatter-gather” some computations

Organized in an OCaml library, with modules, a build system, and all, like some software engineering is happening there …

→ hammerlab/biokepi.

Programming With An EDSL

An EDSL Naturally Comes With Tools

It's Called “Merlin”

It Works With Emacs, Vim, Sublime

Compiling & Running Pipelines

Compiled to more than 3000 Ketrew targets,
with JSON-pipeline registration in a DB, …

Runs for days, then posts to hammerlab/cycledash

The End

Thanks! Questions?

• Happy to hear about Ketrew being useful in any other setting!
• Contribute/complain: https://github.com/hammerlab/ketrew/issues

More Tyxml_js + React

Why Not F# / Scala

• Big runtime
• Type-systems are huge untractable messes (esp. Scala)
• but most importantly: null pointers
  cf. post on F# null handling craziness, up to unsafe compiler optimizations.

Why Not Haskell

• lazy by default → difficult to reason about performance/concurrency
• purity in the Haskell “weak” sense is mostly useless
  
  • looping forver, eating all the memory are much more annoying “side-effects” than writing to a log file or getting the time-of-day
  • putting ⊥ everywhere makes reasoning about pure code actually more difficult
• type-classes in practice:
  used 95% of the time to make the code as unreadable as possible
  (see the Lens library, it looks uglier than perl)
• more unreadability: need to know every possible GHC extension
  (there is even dynamic typing in there!?)
• indentation-based grammar makes code hard to read (blocs > 7 lines)
• no polymorphic variants, labeled/optional arguments, functors …
  how do people handle large code-bases in the long run?

Some OCaml Lessons Learned

Pain:

• Oasis, OCamlbuild
• Camlp4
• Huge Jane-Street-style libraries

Pleasure:

• Pure OCaml, Functors, GADTs
• Ocsigen (minimizing the Camlp4 part)
• Lwt with Error Monad based on Polymorphic Variants
• Bünzli-style small libraries
• Code Generators (ATDgen)
• Opam

Error Monad With Polymorphic Variants

utop> IO.read_file;;
- : string ->
    (string, [> `IO of [> `Read_file_exn of string * exn ] ]) Deferred_result.t

utop> IO.write_file;;
- : string ->
    content:string ->
    (unit, [> `IO of [> `Write_file_exn of string * exn ] ]) Deferred_result.t

utop> System.with_timeout;;
- : float ->
    f:(unit ->
       ('a,
        [> `System of [> `With_timeout of float ] * [> `Exn of exn ]
         | `Timeout of float ]
        as 'error) Deferred_result.t) ->
    ('a, 'error) Deferred_result.t

Polymorphic Variants Are Awesome

utop> let dumb_copy_with_timeout ~seconds ~src ~dest =
        System.with_timeout seconds ~f:(fun () ->
            IO.read_file src
            >>= fun content ->
            IO.write_file dest ~content
          );;
val dumb_copy_with_timeout :
  seconds:float ->
  src:string ->
  dest:string ->
  (unit,
   [> `IO of
        [> `Read_file_exn of string * exn | `Write_file_exn of string * exn ]
    | `System of [> `With_timeout of float ] * [> `Exn of exn ]
    | `Timeout of float ]) Deferred_result.t

Kinda looks like algebraic effects …

Add Constraint

→ Make sure all “systems” and “network” are handled errors within the state machine.

module Run_automaton : sig
  val step :
    t ->
    (bool,
     [> `Database of  Trakeva.Error.t
     | `Database_unavailable of string
     | `Missing_data of Ketrew_pure.Target.id
     | `Target of [> `Deserilization of string ] ]) Deferred_result.t

Feature Request

Now more fashionable with algebraic effects?

Cf. @das_kube's tweet & on mantis.

Want More GATK?

It uploads reports to AWS without your consent.

-et,--phone_home      Run reporting mode (NO_ET|AWS| STDOUT)
-K,--gatk_key           GATK key file required to run with -et NO_ET

Mount Sinai

Mount Sinai

• Among 37_000 employees …
• We are a 15 person lab in the School of Medicine.

Bioinformatics Workflows

Example: somatic variant calling

• Sequence DNA for a tumor and a normal sample
• Find differences: “variants”
• Example application: Cancer Immunotherapy
  
  • Somatic variants → Mutated proteins → distinctive antigens
  • ⇒ Use the mutated regions of cancer proteins to make a peptide vaccine
    i.e. guide the immune system in the right direction.

A Variant

Immune System

Some Cool Stuff Under The Hood

Dynamic linking + first class modules:

• execution backends as “plugins”
• still can avoid dynlink with some build-magic

Fully jump on the PPX bandwagon:

• ppx_deriving_yojson everywhere + functors to force versioning
• code-coverage analysis → rleonid/bisect_ppx
• even js_of_ocaml's very fresh PPX syntax

And …

Polymorphic-Variants → Automaton

State machine encoded with sub-typing

Structural Sub-Typing of States

type passive = [ `Passive of log ]
type active = [ `Active of (passive history * [ `User | `Dependency of id ])]
type evaluating_condition = [
  | active
  | `Tried_to_eval_condition of evaluating_condition history
]
type already_done = [
  | `Already_done of evaluating_condition history
]
...
type killable_state = [
  | passive
  | evaluating_condition
  | building
  | starting
  | running
]
type killing = [
  | `Killing of killable_state history
  | `Tried_to_kill of killing history
]
...
type t = [
  | killing
  | killed
  | killable_state
  | successful_run
  | finishing_state
  | finished
]

Structural Sub-Typing of States

⇒ Pure/total/exceptionless

val transition: state -> (do_some_io * (some_io_result -> state)) 

⇒ There is a test that traverses all the edges and draws a dot-graph

But,

• quite a few “big match-with” functions (for display, counting stuff …)
• bunch of code to simplify and “flatten” the state (Yojson stack-overflowing on Chrome)

GADTs, Hammers, and Nails

type _ t =
  | Fastq_gz: File.t -> fastq_gz  t
  | Fastq: File.t -> fastq  t
  | Bam_sample: string * bam -> bam t
  | Bam_to_fastq: [ `Single | `Paired ] * bam t -> fastq_sample t
  | Paired_end_sample: string * fastq  t * fastq  t -> fastq_sample  t
  | Single_end_sample: string * fastq  t -> fastq_sample  t
  | Gunzip_concat: fastq_gz  t list -> fastq  t
  | Concat_text: fastq  t list -> fastq  t
  | Star: fastq_sample  t -> bam  t
  | Hisat: fastq_sample  t -> bam  t
  | Bwa: bwa_params * fastq_sample  t -> bam  t
  | Bwa_mem: bwa_params * fastq_sample  t -> bam  t
  | Gatk_indel_realigner: bam t -> bam t
  | Picard_mark_duplicates: Picard.Mark_duplicates_settings.t * bam t -> bam t
  | Gatk_bqsr: bam t -> bam t
  | Bam_pair: bam  t * bam  t -> bam_pair  t
  | Somatic_variant_caller: Somatic_variant_caller.t * bam_pair t -> vcf t
  | Germline_variant_caller: Germline_variant_caller.t * bam t -> vcf t

Typed bioinformatics pipelines!

Thanks

Done with github.com/smondet/makmash which is a bunch of hacks on top of

• github.com/ocaml/omd
• github.com/zoggy/higlo

generating a github.com/hakimel/reveal.js presentation.

Meta

• Compiled on Wed, 16 Sep 2015 10:04:08 -0400
• Git: 9cc3a04-dirty