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For disease detection, every molecule counts.

Our molecular counting platform can help quantify nearly undetectable DNA changes, unlocking improvements to non-invasive prenatal screening and liquid biopsy.

Our molecular counting platform can help quantify nearly undetectable DNA changes, unlocking improvements to non-invasive prenatal screening and liquid biopsy.

The Challenge
Some genetic nuances are nearly undetectable in cell-free DNA

Cell-free DNA (cfDNA) are fragments of genetic material that are shed into the bloodstream. Some conditions are easier to detect and quantify with cfDNA as they involve drastic genetic changes and/or are more abundant in the bloodstream. However, other conditions shed tiny and/or sparse DNA fragments into the blood. These conditions can benefit from quantification at the molecular level to confer meaningful observations.

Prenatal

Traditional non-invasive prenatal screening focuses on assessing a fetus’ risk for larger chromosomal changes (e.g., an extra chromosome such as trisomy 21). But several common and severe conditions are the result of much smaller genetic changes that are not as abundant in the maternal bloodstream. Sickle cell disease, for example, is an inherited condition caused by a base pair alteration within a single gene. 

Identifying these tiny changes within cfDNA is complex because the fragments are small and sparse compared to the wildtype variations and vast maternal DNA in the background.

Oncology

It is important to monitor how a patient’s tumor changes over time. Scans are non-invasive and widely used but can present logistical, cost, and radiation challenges. Liquid biopsy tests are a rapidly growing mechanism to non-invasively look at circulating tumor DNA (ctDNA; a type of cfDNA).

Some small but meaningful tumor changes can be challenging to detect as they may be hard to physically see (on scans) or only reflect minimal changes to the amount of ctDNA in the blood (liquid biopsy). Currently available liquid biopsy products for monitoring focus on qualitative measurements that primarily work when the tumor can be surgically removed (minimal residual disease detection), resulting in an unmet medical need when surgical removal is difficult.

Tiny-scale changes call for tiny-scale quantification

BillionToOne’s proprietary molecular counting technology, or Quantitative Counting TemplatesTM (QCTs), quantifies DNA fragments (molecules) to detect conditions caused by tiny DNA variations that can be sparse in the bloodstream. These include pregnancy-related DNA that code for recessively inherited conditions such as sickle cell disease and cystic fibrosis and ctDNA in the case of cancer.

How It Works
molecular counting

An accurate count of disease-related DNA fragments (molecules) in a blood sample can tell us about the status of a patient’s cancer or a fetus’ risk for genetic conditions. Because some fragments are tiny and/or sparse, they must be amplified. However, amplification can confound the challenge of detecting disease as it can be noisy and molecules amplify at different rates. Adding QCTs prior to amplification provides a measurement tool that allows for better quantification after this step to determine how many disease molecules were in the initial sample to begin with. 

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add

Add a specific number of traceable, synthetic DNA fragments called QCTs (n1) into the patient’s blood sample, which contains an unknown number of DNA fragments of interest ( m1) among a vast background of the patient’s genome.

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amplify

Using PCR, the DNA fragments
of interest are amplified at the
same, unknown rate as QCTs.

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count

Count the number of QCTs ( n2) in the amplified sample and divide it by the number added to the original sample. This is the amplification multiplier (x).

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compute

Apply the multiplier (x) from the QCTs
amplification to solve for the number of
DNA fragments of interest in the original
sample ( m1). This involves proprietary
machine learning-enabled bioinformatics
and computation methods.

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A patient's blood stream cell-free DNA

Our molecular counting technology makes our commercially available non-invasive prenatal test, UNITY ScreenTM, possible. UNITY is the only NIPT that can assess fetal risk for recessive conditions and aneuploidies from a single maternal blood draw.
We are also actively looking for research collaboration partners for our new research liquid biopsy products, Northstar SelectTM and Northstar ResponseTM.

Publications

Single-Gene NIPT (sgNIPT) Analytical Validation

Published in Nature Scientific Reports

October 7, 2019

A novel high-throughput molecular counting method with single base-pair resolution enables accurate single-gene NIPT

  • Proof of concept for QCT platform necessary for the technology of sgNIPT
  • Analytical validity of sgNIPT with an estimated sensitivity of >98% and specificity of >99%
Read Article for A novel high-throughput molecular counting method with single base-pair resolution enables accurate single-gene NIPT
First page of article: A novel high-throughput molecular counting method with single base pair resolution enables accurate single-gene NIPT

Sickle Cell Disease Validation

Published in American Journal of Hematology

April 16, 2022

Validation of single-gene noninvasive prenatal testing for sickle cell disease

  • sgNIPT accurately identified all affected pregnancies as high risk at a greater than 9 in 10 risk
  • sgNIPT accurately identified all unaffected pregnancies as low or decreased risk
Read Article for Validation of single-gene noninvasive prenatal testing for sickle cell disease
First page of article: Validation of single-gene noninvasive prenatal testing for sickle cell disease

sgNIPT Health Economics

Published in Journal of Medical Economics

March 23, 2022

Reflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower cost

  • Carrier screening with reflex to sgNIPT resulted in an estimated $37.6M saving per 100,000 pregnancies compared to traditional carrier screening in a model comparison
  • The cost to detect one affected pregnancy by carrier screening with reflex to sgNIPT was 62% lower than traditional carrier screening
Read Article for Reflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower cost
First page of article Reflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower cost

Our Proprietary Technology Platforms

  1. QCT technology

    Quantitative counting templates for flexible, accurate and high throughput combined sequencing and counting of DNA molecules.
  2. Dilution tagging technology

    Application of statistical compression algorithms during physical DNA sample preparation. Compresses DNA samples with high dynamic range while preserving initial signal. Enables low cost sequencing of DNA samples with rare sequences without loss of quantitative information.
  3. Spike-in technology

    Synthetic DNA controls custom made for each assay and added to every patient sample. These DNA controls enable per patient correction factors when determining copy number of targeted genes.
  4. qSanger technology

    Combines spike-in technology with custom-built, proprietary signal processing and applies it to Sanger sequencing and capillary electrophoresis, bringing the power of quantitation to previously qualitative technologies. This approach brings NGS-level precision to easy-to-deploy technologies and enables their use as low-cost, high-throughput, diagnostic tools.