Locus Science: OpenCLIA Rare Diseases

OpenCLIA RD is a bioinformatics software package for any CAP/CLIA clinical  diagnostic labs that does not require technical expertise to use by clinical staff. The pipeline ingests NGS data in the form of FASTQ or VCF for any WES/WGS library (validated for multiple vendors, including Agilent and Twist Bioscience) and returns a provisional diagnostic clinical report within minutes for the top causal variants. The provisional report can be used to make rapid clinical decisions by a physician, whereas a fully reviewed and signed CLIA director report follows shortly after. Additionally, OpenCLIA RD automatically incorporates access to a genetic counselor for users to interpret their results with a licensed clinician in all 50 states in the US. The software rapidly differentiates variants and keeps track of any updated literature in real-time to autonomously classify/re-classify variants. Finally, our collection kits simply involve a finger prick blood collection (partnered with Neoteryx Mitra).

We are building enterprise-grade rare disease diagnostics. We pair our OpenCLIA RD platform to pharma companies who are involved in rare disease therapeutics to truly capture patient-centric value. We also scale to hundreds of CAP/CLIA labs across the US and aim to expand globally via IVDR regulations. In rare diseases, it takes on average ~5 years and ~8 specialists to get a diagnosis. For many people, it's longer and some do not ever get a right answer. Current paradigms puts the burden of diagnosis on the patient and caregiver to navigate/advocate for their own health. Many rare disease phenotypes are not catalogued with a respective genotype. An undiagnosed or misdiagnosed patient undergoes a hospital visit after hospital visit and test after test, whereby the phenotype leads to an EHR analysis, subsequent to a clinical review, subsequent to a patient being contacted for a diagnostic assay, then the patient agrees to testing, then a gap in scientific knowledge for the rare diseases exists... and the patient undergoes a diagnostic odyssey that could last for years.

We're changing this by a) rapid sample collection, b) rapid WES/WGS, and c) rapid sequencing data analysis to classify/re-classify variants of all classes. 

Our solution is a clinical-grade bioinformatics pipeline that any CAP/CLIA accredited lab can use. We start from raw primary data (FASTQ) or secondary/tertiary data (VCF/BAM) such that anyone can upload and a provisional report is generated in minutes. The goal of the provisional report is to rapidly screen for pathogenic and likely pathogenic variants by using NLP AI and 4 different clinical bioinformatics pipelines that operate in parallel from the same data set. We use BaseSpace to aggregate all sample data directly from Illumina workflows, DRAGEN/Sentieon/Enliter for triple secondary analysis, FastQC + MultiQC for robust QA/QC, Genoox + Franklin for first source of tertiary analysis, VarSome Clinical for second source of tertiary analysis, Illumina Variant Interpretar for QA/QC of tertiary analysis (triple check), and integration of DNAvisit for Genetic Counseling services in real-time with telehealth options. 

Simply put, we make bioinformatics very accessible to CAP/CLIA labs where it matters the most for genetic sequencing, since these are the only labs in the US where a clinical decision matters. We understand that provisional diagnostics followed by a full clinical report will be the new norm for rapid screening and diagnosis of mass populations who may be afflicted with a rare disease.

We partnered with DNAsimple to identify over 180K people (so far) who have a high probability of having a rare disease (based on EMR and family members). We have a novel collection device (Neoteryx Mitra) to rapidly deploy over zip codes via USPS with a "blanket" approach (we can do this for free and cheaply). We have CAP/CLIA sequencing to conduct the high-throughput wetlab work at scale or can partner with any CAP/CLIA lab (and academic lab) to deploy such wetlab. We can capture patients who are struggling from misdiagnosis or no diagnosis yet a phenotype exists - we can route these patients for definitive diagnoses whereby a therapeutic option may exist from a pharma company. We know that low-income and disproportionate populations are not able to afford clinical sequencing > this is what we are bringing to market at scale with a cost-effective solution. We can a) capture the patient sample, b) conduct the high-throughput WES/WGS sequencing, and c) provide provisional diagnostic and full clinical grade reports within minutes with options for genetic counselors as needed. 

We developed this solution knowing that orphan drug designations are continuously repurposed by pharma companies, yet pharma companies have a hard time identifying patient populations who can benefit from such drugs. We understand that the diagnostic odyssey in rare diseases is a battle that is fought by the patient - we're trying to ease this burden via bioinformatics pipelines and scalable solutions that are specific for rare diseases and scalable for the 7 billion human population, knowing that 1 in 10 are affected. Our solution is simple because the sample collection is unique and efficient and the bioinformatics solution is robust with built-in redundancies that are all clinical-grade. 

Overall, we want to categorize these variants more efficiently and effectively so that the public knowledge can be used by other clinicians to quickly diagnosis rare diseases.

We've identified over 100K rare disease patients with IRB approved questionnaires and can collect samples as needed. See our partner rare disease dashboard here: https://artemiosisoniii.shinya...

We have a novel blood microsampling collection device that is easily deployable by EDDM USPS mail. See here: www.neoteryx.com

We build a proprietary rapid WES/WGS bioinformatics pipeline for rare disease sequencing diagnostics by using a combination of BaseSpace, DRAGEN/Sentieon/Enliter, Genoox/Franklin, VarSome Clinical, and DNAvisit to provide an all-inclusive provisional diagnostic and clinical diagnostic report that is CAP/CLIA grade with ABMG board-certified director sign-outs. www.locusscience.com

We can scale our solution within Amazon AWS S3.

We built the prototype of our solution while gathering intelligence and building more value-adds that are clinically applicable for a physician/geneticist to make actionable decisions. We partnered with multiple providers to build redundancies in our pipeline. We conducted a clinical validation of our solution by using historical clinical samples of known rare diseases, Coriell validation samples of known rare diseases, tested various aspects of our pipeline caller (i.e. CNV, SV, SNVs/indels, and more), tested a robust list of QA/QC metrics, and made sure that that our solution is super user-friendly for anyone who has never conducted any bioinformatics drylab work.

Our goal was to make the solution easy to use for novices, which is the number 1 barrier in clinical lab settings for the adoption of NGS platforms. Most people can do the wetlab work, but only a few can conduct the analysis. We're changing this with OpenCLIA RD!

We are the first to create a NGS bioinformatics solution for rare diseases that provide autonomous provisional diagnoses for clinicians, physicians and geneticists at the clinical level. We are also the first to fully incorporate an end-to-end solution for novel sample capture, high-throughput sequencing, and automated clinical reporting. From the time a FASTQ/VCF file is inputted into our bioinformatics pipeline, we can have a provisional diagnostic in MINUTES so that the clinician can make actionable decisions instead of waiting for weeks for a full report. We can diagnose pathogenic mutations in real-time from the most up-to-date literature. We utilize over 100+ databases for variant curation sources plus 100+ different QA/QC tools and build multiple redundancies to make sure we make highly accurate calls. 

Our business model is to standardize the way bioinformatics for WES/WGS is conducted inside of CAP/CLIA labs within the US. By standardizing NGS QA/QC and rare disease pipelines, we control the versioning as well as the user-friendliness (no coding needed) so that our solution can be deployed to any CAP/CLIA lab with an Illumina sequencer (90% of market). By providing our CAP/CLIA labs with a "pay-per-click" model, we are changing the way labs an scale at affordable pricing without any upfront costs. 

We also have our own sample collection solution that we can deploy to any CAP/CLIA lab and integrate an entire LIMS for NGS WES/WGS. The rare disease space is highly underserved in the bioinformatics realm due to complicated and custom algorithms by labs. 

Our solution uses the following software stack that is integrated into a single workflow with multiple parallel redundancies (for cross-checks and options):

1. BaseSpace - data storage and BCL2FASTQ conversion

2. DRAGEN - secondary analysis for FASTQ to VCF/BAM

3. Sentieon - secondary analysis for FASTQ to VCF/BAM (parallel)

4. ENLITER - secondary analysis (parallel redundancy)

5. FastQC - QC check

6. MultiQC - QC check

7. Genoox + Franklin - workflow automation and processing

8. VarSome Clinical - workflow automation parallel redundancy

9. Illumina Variant Interpreter - background optional QC parallel redundancy

10. DNAvisit - genetic counseling integration and telehealth access

11. Map Align + Small Variant Caller

12. CNV Caller

13. SV Caller

14. Expansion Hunter

15. CYP2D6 Genotyping

16. Nirvana Annotation

17. Haplotype Caller

18. RTG vcfeval tool

19. vcf-compare

20. hap.py benchmarking

21. 100+ additional databases for genomic and protein predictions and other variant curation databases.

22. 100+ in silico prediction tools with additional automated databases

23. Over 50+ QA/QC checks for the entire end-to-end process

Our solution can also use the new VAMS microsampling device to scale to the mass population for simple blood collection (Neoteryx Mitra device).

Here is one such evidence of a similar solution, yet not in an open-source manner: http://www.diploid.com/moon

Another useful academic paper is here: https://stm.sciencemag.org/con...

All of our software stack is listed above, whereby you can find more information for each with a simple Google. Our proprietary method links everything together into an autonomous workflow while capturing clinical director sign-outs. 

We've identified the possible risks and have overcome them with HIPAA compliant and ISO certified products in addition to having several BAAs executed with all of our software use. Data integrity and protection are secure and streamlined through common practices in the genomic sequencing space.

Other risks may include misdiagnosis from rapid provisional diagnostic reports. However, the risk is mitigated with orthogonal technologies that are specific to a pathogenic variant that can double-confirm the disease variant. This is part of our SOP. We mitigate any risks to rapid reporting of "pathogenic" and "likely pathogenic" variants with orthogonal methods. Likewise, since this is a screening tool to capture patients who can benefit from therapies, we also understand that variants may be missed by rapid provisional reporting. However, we mitigate this risk with double-confirmation from a board certified geneticist from the reflex full reporting sign-out path as part of our SOP.

Ethical risks are addressed, as many patients who are in the diagnostic odyssey state are unable to afford classical NGS. We offer this path the clinical level with the support of a genetic counselor during the entire process. Therefore, our clinical path involves multiple licensed stakeholders (physicians, lab directors, regulatory directors, licensed genetic counselors), and our research path offers the same services, albeit at a lower cost for academic groups who are conducting GWAS studies who need the robust clinical SOPs.

Currently serving: 158 clinical patient samples as validation

In one year: 100,000+ clinical and RUO patient samples from clinical and academic laboratories

In five years: the entirety of the ~4M neonatal births that occur in the US every year + those with existing rare diseases who need a definitive diagnosis (~20M samples per year from a variety of industry partnerships)

Our impact goals are sustainable partnerships with those facilities that have NGS capabilities. As long as a facility has an NGS instrument (Illumina-bases platform), then we will deploy our solution for free and offer the clinical services at-cost. This is a very reachable goal given partnerships with pharma (for clinical trials and research), with academia (since all academic institutions have NGS cores that are very affordable to use), and CLIA labs (who are strongly looking for easy and robust bioinformatics solutions). We have partnerships within each of these categories. We want to scale such partnerships across the US and use the pharma partnerships to scale across the world (i.e. Covance and Quest).

Our impact will be measured by the number of patients that we either initially diagnosis with a rare disease or definitively diagnosis an existing rare disease that the patient isn't aware of yet. We show this with a metric called the "diagnostic utility rate". We expect this rate to be >60%+ (as opposed to 0% from  those living the diagnostic odyssey in the rare diseases space).

Our impact will also be measured with any pharma partner operating in the rare disease space. We fully recognize that the pharma rare disease operator needs a way to identify patients who can benefit from their therapies > this is EXACTLY why we built this autonomous solution with OpenCLIA RD for rare disease genetic/phenotypic diagnosis with clinical reports that are actionable.

We are measuring our progress with the number of variants that we can classify on an actionable basis. However, the main indicator is the clinical diagnostic utility rate - this is the metric that demonstrates our viability within a clinical diagnostic market. It is also the main regulatory metric within CAP/CLIA submissions.

Additionally, we have multiple parallel bioinformatics technical pathways that we offer in a fully transparent and visible manner > we WANT people to learn our process and how we do it at a clinical level, but at the same time, offer the set-up and installation  on our end for an easy to use and operable platform as an end-to-end solution. There is no one in  the space doing this today > we are the first company to do this and carry any regulatory submissions of the lab forward. We are truly scaling this across the CAP/CLIA setting.

As for UN goals, one of the main initiatives is ACCESS to sequencing technology and reporting. Many underserved and poor populations do not have access to genetic sequencing and genomic bioinformatics technologies. We want to enable that access to ALL populations. We also understand that prenatal genetic diagnosis is also not available to the underserved women populations around the world > having such access for diagnosis can reduce clinical burden via non-invasive prenatal diagnosis/screening through sequencing.

Mohammed Khalid - CEO

Others (private)

Our CEO is an expert in supply chain and logistics, with both a BS and MS in Accounting and Finance from Rutgers. He has managed worldwide trade initiatives to scale e-commerce solutions into multi-million dollar revenue streams. His experience is pertinent for diagnostic global scaling.

We have access to several CAP/CLIA partners across the US, pharma groups, CROs and academic institutions. We also have strong vendor relationships with our consumables providers to develop unit economics for scaling across the world. 

Our entire team is passionate about genetics and genomics initiatives. We come from resource-stricken environments and never had access to great healthcare (we were both on "charity care" during the Clinton era and the bulk of our childhood and teens). After being college-educated, we understand how much value we could provide on the  genomics front to all healthcare consumers. We know that a therapeutic agent exists, but most people cannot get access due to poor diagnostics. We are supercharged in changing this paradigm due to technical, regulatory, commercial and general knowledge hurdles that exist within this stakeholder assessment mantra for diagnostics.

Our leadership has a strong focus on open-sourcing diagnostics that are of clinical grade. We started the "OpenCLIA" idea knowing that the US is the only  country that has the most robust number of LDTs, but all of these LDT submissions are not open-source. We know that there are a finite number of routine diagnostic tests that we could open-source and  submit to regulatory agencies for approval, then make our validation  and submission documents fully transparent and open-source so that others can use them for their advantage. At the same time, we offer the  service to help  with any implementation.

This is how we are approaching OpenCLIA RD for our rare diseases program. With the COVID pandemic, we understand how crucial it is to gain access to sequence information  for the  PCR primers/probes that not many were willing to share. The CDC took the first initial efforts to partner with IDT to scale this solution. We are doing the same with genetic/genomic sequencing technologies, all while making sure that we are regulatory compliant within CAP/CLIA settings.

Our bioinformatics platform is also very robust as an RUO tool  for any pharma/academic partner (even CAP/CLIA) who wish to use "base" product and bring it onboard as an LDT into their own lab. We are very inclusive with our methodical approach.

No, but we are led by an expert within the rare disease space who has significant ties to a wealth of rare disease organizations (i.e. Wilson's Disease Association, several CM-TMA groups, rare bleeding disorder associations and more).

The Horizon Prize is specifically within our remit for rare disease diagnosis. We are in the field of rapid genetic diagnostics and screening from high-through sequencing technologies. We are applying to this prize given that there is significant synergies with Horizon, the application  theme, and the overarching long-term efforts to scale rapid, autonomous, rare-disease genomic sequencing diagnostics. We are well within our wheelhouse for this  prize with high-impact value while also benefiting from a potential partner in Horizon.

We want to use our platform as a capability for pharma partners (i.e. Horizon) for the screening and diagnosis of rare disease patient samples to identify such patients who could benefit from therapies.

We would also like the funding to work out of an incubator space within Princeton, NJ given that the top 16 pharma partners are here.

Finally, we want to bring some new chemistries for wet-lab sequencing in-house. Even though we strictly operate within the bioinformatics space, we would like to start creating value and efficiency in the wetlab chemistry space (which we also have significant experience and technical knowledge, yet the barrier to entry for capex is too high). 

Overall, we will use the funds to build an entire autonomous sequencing (NGS) program in  the long-term, while creating the strongest scalable bioinformatics solutions for pharma/CLIA labs in the near-term.

Horizon Therapeutics and any other rare disease pharmaceutical organization in the world.

LabCorp and Quest (since they have market access at scale already).

Any CAP/CLIA lab that is looking for help with NGS/bioinformatics at the clinical grade level.