Datapunk Circuits: A Multi-Dimensional, Open-

Source, Genomic Database for Clinical Investigation

By Peter D’Adamo, ND

T O W N S E N D L E T T E R

The Center of Excellence in Generative Medicine (COEGM) at the University

of Bridgeport College of Naturopathic Medicine is rapidly becoming the leading
research and industry leader in naturopathic clinical bioinformatics. Much of
the utility and pertinence of the software solutions produced by the COE lies in
its recognition that today’s physicians cannot easily parse increasingly available
large datasets (such as produced by genome or microbiome reporting services)
in any sort of real-time efficient manner. This is indeed a dilemma, as ‘big data’
approaches (in particular those employing machine learning algorithms) are
increasingly pointing the way to the possibilities of more precise treatment
based on high-value considerations.

One possible approach to the problem was a more 'generative' approach, as

advanced by William Wimsatt: That we are limited beings and the world we try
to understand is complex.(1) For Wimsatt, robustness (believing that a particular
apple exists because we can see it, feel it, smell it, taste it, and hear it crunch
when we eat it) is measured by the multidimensionality of the data models: The
more we can detect things in multiple ways, the more we are inclined to believe
they exist. Closely connected to robustness are the heuristics, rules of thumb
that we use to think about the world and which are foundational to his
epistemology.

Heuristics can be wrong or biased but tend to work well when applied to what is
robust in the world. For example, a basic generative heuristic is derived from
cybernetics and is known as 'law of requisite variety.' In essence, it mandates
that the number of states of a control mechanism must be greater than or equal
to the number of states in the system being controlled. This heuristic, along with
personalized clinical data and robust molecular network data, permits the design
of computationally generated, personalized, multi-axis polypharmacy, well-
suited for natural products, where the therapeutic index of the agent
combination rises significantly, but the overall safety profile remains essentially
unaltered.

The generative paradigm works well in addressing the challenge of how to

approach the onslaught of 'big data' into the clinical workspace. Person-specific
genomic, metabolomic, and microbiome data files can easily reach into the
hundreds of megabytes of information. Clearly, we need analytic tools capable
of automating the basic handling, analysis, and integration of this wealth of
information. The challenge is daunting, but the potential rewards are almost
unfathomable: A more precise clinical impression, where (paradoxically) 'more
data is better than better data,' and broadly applied evidence-based conclusions
are only one part of the evaluation framework.

Over the past five years in partnership with Datapunk Bioinformatics LLC, the
COEGM has developed a variety of computational tools for precision medicine
using generative-based algorithms; some proprietary, such as the well-known
and regarded Opus23 genomic development platform, along with its two add-on
analytic modules, Utopia (microbiome) and Icarus (metabolome). Other apps on
the servers are open source and free-to-use.

On August 25, 2018, the COEGM announced the release of ‘Circuits’ a gene-
based open source platform combining genomic data in a variety of robust
dimensions. Circuits is web-based, has an imaginative and intuitive user
interface, and is free to use. I’d like to use the rest of this article to introduce
and describe the capabilities of Circuits and invite the readers of the Townsend
Letter to explore its possibilities.

The Interface

Circuits resides at the web address https://www.datapunk.net/circuits and can be

accessed by any modern browser. Because of the data depiction density, it is not
optimized for small handheld smart phones, and it is recommended that a desk
or laptop machine be used to access the app.

Circuits’ initial presentation appears as shown below. In its default state,

Circuits displays the data for the gene MTOR (mammalian target of rapamycin)
as a place-filler. Immediately below the title slug, Circuits displays the known
PPI (protein-protein interactions) associated with the target gene (in this case
MTOR) as a Cytoscape network. Afferent nodes are shaded red whilst efferent
nodes are colored green. This network is an effective way to navigate Circuits
as any node will bring up its related gene and load it into the main window.
Users can also search for any gene/protein by using the traditional search input
at the top right of the screen. To help users refine their query, the search feature
will autocomplete over 30K currently recognized gene symbols.
Scrolling downwards, the user will see the six scrollable panes that contain the
data mash-ups. From the top left we can see a detailed description of the gene,
and across from that, a pane that depicts the available data on agents associated
with the expression of the gene. This is a unique, human-curated database that
was originally developed for use with the Opus23 platform.

Circuits employs a variety of modal popups to provide additional contextual

data. Clicking on any agent will trigger a popup window that draws a unique
radar plot that we call the ‘genomic logo’ of the agent. This logo depicts the
strength, action, and targets of the indicated agent, using a complex algorithm
based on study design, scope, and subject type.

The next row of two panes further down show disease associations and
clinically relevant SNPs (single nucleotide polymorphisms) associated with the
target gene. Pathology data is derived from ClinVar, OMIM and GWAS, while
SNP associations are from GWAS and the exclusive human-curated SNP
database developed for use in the Opus23 program. Clicking on a hyperlinked
disease or SNP will also launch informational popups.

The next row of panes highlights, on the left, any adverse drug reactions linked
to specific polymorphisms of the target gene and known tissue and organ
distributions of the target gene. As with all internal hyperlinks, clicking on any
link in these panes will trigger a popup containing additional data.

The next row of informational panes shows, on the left, pathway regulations
associated with the target gene pathway and its effect (either up-regulation or
down-regulation). The bottom right pane shows etiological links associated with
the target gene that are inferred via the target gene’s disease associations.

The final single pane displays HMDB (Human Metabolome Database) linkages
to the target gene. Clicking on the metabolite common name will trigger a
popup display detailing the metabolite.

The Data

Most of the data used by Circuits was developed initially for use by the Opus23
application from publicly available repositories. Exceptions include the SNP
and agent expression datasets, which were developed entirely by Datapunk
human curators. The PPI, etiome, and diseaseome datasets were enriched by
combining multiple source data, in some cases programmatically through
structured machine earning. A few of the larger sources are listed as
references.(2-8) It should be noted that the publication date of several of the
references may be over several years old; however, these articles typically
announce and describe the dataset, the actual databases they represent are
almost all continuously updated; and through its network of application
programming interfaces (APIs), so is Circuits.

Test-Driving Circuits

Readers are encouraged to ‘surf’ Circuits and explore the target genes that seem
more interesting. Click away! However here are a few hard links to help get you
started.

· The ABO ‘secretor’ gene (FUT2)

https://www.datapunk.net/circuits/index.pl?FUT2

· Mitochondrial enzymes that catalyze the oxidative deamination of amines,

such as dopamine, norepinephrine, and serotonin (MAOA and MAOB)

https://www.datapunk.net/circuits/index.pl?MAOA

https://www.datapunk.net/circuits/index.pl?MAOB

· Catechol-O-methyltransferase (COMT) catalyzes the transfer of a methyl

group from S-adenosylmethionine to catecholamines, including the
neurotransmitters dopamine, epinephrine, and norepinephrine.

https://www.datapunk.net/circuits/index.pl?COMT

· PPAR-gamma is a regulator of adipocyte differentiation. Additionally,

PPAR-gamma has been implicated in the pathology of numerous diseases
including obesity, diabetes, atherosclerosis, and cancer.

https://www.datapunk.net/circuits/index.pl?PPARG

· MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-

methyltetrahydrofolate, a co-substrate for homocysteine (HCy) remethylation to
methionine.

https://www.datapunk.net/circuits/index.pl?MTHFR
The Code

The server-side portion of Circuits was written in the Perl language, the ‘Swiss
Army Chainsaw’ of bioinformatics. Client-side elements, such as network
depictions and graphic displays of information, were coded in JavaScript using
the Cytoscape JS and HighCharts JS frameworks. The PPI network was
normalized using the Graphviz graphing package and the CPAN Graph module.

The Easter Egg

Users can store particularly interesting or important genes in a non-tracking

cookie ‘wallet,’ for long-term use, thus allowing them to retrace prior
investigations.

I hope the Townsend Letter readers have half as much fun exploring Circuits as
I did envisioning and coding it. We at the Pathfinder Scholar Program at the
COEGM are planning on expanding our open-source offerings to include a
microbiota explorer that uses taxon interaction networks and Markov chains to
produce a multigenerational approach to eubiosis; and a small metabolite
(metabolome) explorer that employs machine learning classifiers to generate
metabolic patterning characteristics. I’ll make sure to alert the readers when
these tools become available.

References

1. Wimsatt W. Re-Engineering Philosophy for Limited Beings: Piecewise

Approximations to Reality. Cambridge: Harvard University Press. 2007

2. Landrum MJ, et al. ClinVar: improving access to variant interpretations

and supporting evidence. Nucleic Acids Res. 2018 Jan 4. PubMed PMID:
29165669.

3. Prasad, TSK, et al. Human Protein Reference Database - 2009 Update.

Nucleic Acids Research. 2009;37, D767-72.

4. Liu YI1, Wise PH, Butte AJ. The "etiome": identification and clustering of
human disease etiological factors. BMC Bioinformatics. 2009 Feb 5;10 Suppl
2:S14.
5. Kaplun A, et al. PGMD: a comprehensive manually curated
pharmacogenomic database. The Pharmacogenomics Journal. 2016;16:124–
128.

6. Thul PJ, Lindskog C. The human protein atlas: A spatial map of the human
proteome. Protein Sci. 2018 Jan;27(1):233-244.

7. Barabási A-L, Gulbahce N, Loscalzo J. Network Medicine: A Network-

based Approach to Human Disease. BMC Bioinformatics. 2009; 10(Suppl 2):
S14.

8. Wishart DS, et al., HMDB 4.0 — The Human Metabolome Database for
2018. Nucleic Acids Res. 2018. Jan 4;46(D1):D608-17. 29140435

Peter J. D’Adamo, ND

Distinguished Professor of Clinical Medicine and Bioinformatics

Center of Excellence in Generative Medicine

University of Bridgeport, College of Naturopathic Medicine

https://www.coegm.com/

https://www.thetownsendletter.com/426-datapunk-circuits-bioinformatics-
generative-medicine-excellence-database