Most diseases have a genetic component. Genetic risk scores quantify the degree of risk conferred through an individual’s genes.
The human genome contains several million genetic markers that commonly vary across individuals and influence the risk of common diseases. Individually, each of these associated single nucleotide polymorphisms (SNPs) has a small impact on disease risk. Their combined effect, calculated as a polygenic risk score (PRS), is frequently the best genetic estimate of disease risk, providing more predictive value than any single gene marker alone [1, 2, 3]. Genetic risk scores often outperform traditional clinical risk factors like smoking, BMI, and family history [3, 4]. This is a new development, over the last 5 years genome sequencing has become more affordable, allowing study sizes to grow to the order of hundreds of thousands of individuals. These larger study sizes provided large amounts of data and afforded the development of more accurate genetic risk scores [5, 6].
Learn more about genetic risk scores through a visual explainer.
Orchid tests for genetic susceptibility to the most common conditions based on many genes instead of rare genetic disorders caused by single genes.
Historically, clinical genetics has focused on identifying rare genetic variants that diagnose a rare genetic disease. Monogenic diseases such as cystic fibrosis or spinal muscular atrophy can be diagnosed by interrogating genetic variation within single genes. These conditions may have autosomal dominant, autosomal recessive, or X-linked inheritance patterns. These are the tests that are usually ordered by physicians for individuals at risk of an inherited mutation, or as part of preconception or prenatal counseling.
However, the vast majority of diseases are not controlled by the presence or absence of a single gene. Most common disease susceptibility is governed by small changes in dozens to millions of locations across the genome .
A genetic risk score aggregates the effects of tens to thousands of genetic variants that mediate their effects through many genes: this is what is meant by a “polygenic” disease architecture .
Learn more with a deeper dive into our science.
An elevated genetic risk score identifies individuals with a genetic susceptibility to a disease of interest, however it is not a diagnosis of a disease.
While anyone can develop any of these conditions, genetics can tell us whether an individual has a combination of certain genetic markers that increase or decrease susceptibility to these conditions. Genetic risks are similar to other risk factors — a smoking history makes an individual more likely to develop lung cancer, for example.
Knowing this information can help individuals proactively manage their health and if desired, seek mitigation strategies to lower genetic risk for their future children, thus decreasing risk of disease development .
Statistical geneticists develop genetic risk scores using cohorts of hundreds of thousands of individuals who have sequence data paired with physician verified diagnoses.
Statistical tests are performed to find variants that are found in cases (individuals with the disease of interest) at higher rates than in controls (individuals without the disease of interest).
This study design is called a genome-wide association study (GWAS) . There is no single way to develop a polygenic risk score model, but the process generally involves:
Reducing the impact of potential confounding variables. In this case, non-genetic factors like age, socioeconomic status, or geography
Identifying a set of genetic variants with a strong association to the disease outcome
Quantifying the extent to which each genetic variant either increases or decreases disease risk
Once a genetic risk score has been developed, it must be tested on a separate population that has also been sequenced and has physician verified diagnostic records. This is known as a “validation dataset” and helps answer the question: “is this genetic risk score as predictive on this population as it was on the original cohort used to develop the model? ”
Using data from hundreds of thousands of individuals, we see that individuals with an elevated genetic risk for a particular condition are 2 to 5 times more likely to develop that given condition than the average population.
Genetic risk scores aggregate the effects of dozens to millions of variants across the genome to estimate overall risk more accurately than monogenic (single gene) status alone [1, 2, 3]. Genetic risk scores outperform conventional clinical risk factors [3, 4].
The evidence supporting genetic risk scores is based on curated databases of hundreds of thousands of individual’s genetic sequencing data paired with physician verified diagnoses. Large-scale studies have reproducibly found that genetic risk score percentile stratifies and predicts the fraction of individuals that develop a condition over time.
To illustrate, the figure below maps the percentile of a genetic risk score for coronary artery disease to the prevalence of coronary artery disease. The light blue dots represent actual patient cases, while the dark blue dots represent the predicted prevalence using the genetic risk score .
Khera A.V., et al. (2018); Supplementary Figure 2
We continually review the latest research in genomics — identifying results that meet our stringent quality standards. We only incorporate results reproduced by several research groups and based on population sizes of more than 10,000 individuals.
Learn more with a deeper dive into our science.
Our Embryo Report measures genetic predisposition for the top, common chronic conditions not included in other embryo genetic testing.
Currently, embryo testing involves the ability to screen for aneuploidy, monogenic conditions, and structural rearrangements. These tests are known as PGT-A, PGT-M, and PGT-SR, respectively. PGT-A is included in Orchid’s Embryo Report and is applicable to any couple, while PGT-M and PGT-SR are done for specific clinical indications.
Parents can safely and naturally reduce their future children’s riskfor the top 10 most common diseases.
Coronary Artery Disease
Type 2 Diabetes
Type 2 Diabetes
Inflammatory Bowel Disease
Besides reporting on genetic risks for common conditions, our embryo report also evaluates the number of chromosomes within each embryo. This is commonly referred to as preimplantation genetic testing for aneuploidy (PGT-A).
Results can help clinicians like you counsel patients on each embryo’s genetic health profile and inform your patients’ transfer plans.
A reproductive endocrinologist will be able to use the results of Orchid’s genetic risk assessment of embryos to assist with patient decision-making in embryo selection. The patient and physician can use this information to make an informed decision about which embryo to consider transferring first, based on the results of the report.
Orchid also offers preconception testing with our Couple Report that screens and identifies couples expected to have children with elevated genetic risk for a specific condition.
Much like carrier screening, preconception testing identifies “at risk” couples who may choose to mitigate their future child’s genetic risk through embryo creation, screening and transfer prioritization.
Learn more about our Couple Report.
We recognize that there is a subset of patients with a limited number of blastocysts available for biopsy. In these patients, the utility of using advanced embryo screening for disease risk mitigation will be limited.
At the same time, there is a growing number of couples seeking IVF treatment at younger ages, for reasons beyond infertility — fertility preservation, genetic screening, LGBTQ family building are rapidly growing indications for IVF procedures. Many of these patients create multiple high-quality embryos in a given IVF cycle. In these scenarios, embryo screening may be suitable as a planning tool to provide future parents access to informed information and choice. As with any tool, your clinical judgement is vital to help serve your patients best.
Yes. Orchid includes a personalized video walk through with a board-certified genetic counselor with every report. Patients also have access to speak with a genetic counselor about their results.
Orchid reports come with online result review scheduling that patients love. Orchid reports include the most comprehensive genetic information available, that will satisfy the most discerning clientele and keep your practice competitive with the top centers around the world.
Genetic risk reductions vary depending on the genetic architecture of the condition and the genetics of each individual couple. Some couples are at risk of having children in the top 10% of genetic risk, or above the 90th percentile, for a certain common condition.
We aim to help understand the genetic risk of individual embryos to, if available, prioritize transfer of embryos with lower genetic risks.
Orchid’s genetic risk assessment priority is based on deprioritizing embryos with:
1. Chromosomal abnormalities
2. Increased genetic predisposition for common conditions
Typically, we do not find that couples are at high genetic risk for multiple conditions at once. This means that it is rare for an embryo to have significantly increased genetic predispositions relative to baseline risk for two conditions or more.
In the rare case that a couple is identified to have embryos with elevated genetic risk for multiple conditions, determining the couple's values is critical to develop an embryo selection plan that best supports patient autonomy.
Lowering genetic risk for one condition is unlikely to impact risk for other conditions. This is because Orchid focuses on mitigating risk for embryos in the highest percentiles of genetic risk and it is unlikely that an embryo has an elevated genetic risk for multiple conditions.
To better understand why this is, here is the relationship between the prevalence rate of a condition (what fraction of individuals are affected with the disease) and the percentile of the genetic risk score. As you can see below, the curve is largely flat (indicating a small change in risk), up until the 90th percentile, where a sharp increase in risk emerges. While the curve and numbers vary slightly by condition, this pattern applies to all conditions tested.
The genetic health assessment provided on Orchid’s Embryo Report is available to help you make an informed decision about which embryo to consider transferring first. It does not preclude the transfer of embryos with a higher genetic risk.
Embryo transfer decision-making is ultimately driven by the reproductive endocrinologist’s and embryologist’s recommendations and patients’ desires. These decisions are often made on a discretionary case-by-case basis.
We recommend excluding couples that are expected to have 3 embryos or fewer suitable for preimplantation genetic testing. We do not expect to provide substantial genetic prioritization utility for such couples.
Yes. Couples can opt to receive embryo results unmasked or blinded. If the couple opts for blinded non-disclosure, they are still able to transfer the embryo with the lowest genetic risks based on Orchid’s genetic reports, without revealing the contents of the report. If a child is born from that embryo, he or she may opt to unmask the results after age 18.
Our mission is to help couples give their future children the best shot of a healthy life. In many cases, embryo screening is able to substantially reduce potential genetic risks for the next generation.
If a couple who pursues embryo screening only has embryos with elevated genetic risk for specific conditions, and elects to transfer such an embryo, the information can guide proactive management if the development of the condition does occur. Increased awareness, screening, and lifestyle modifications can potentially help prevent or identify conditions early.
Orchid is deeply invested in operating at the highest ethical and scientific standards. Our mission is to help couples give their future children the best shot of a healthy life, without inheriting a predisposition to disease.
Prevention of adult-onset disease through embryo screening and IVF is not new. Adult-onset disorders now represent over 20% of all preimplantation genetic testing for monogenic disorders (PGT-M) cases, with the most common indication being for cancer predisposition syndromes (Rechitsky & Kuliev, 2019).
Over the last 20 years, the field has advanced from the detection of very rare mutations to the capability to measure genetic susceptibility for common conditions. From a reproductive freedom perspective, we stand for a couple’s right to have access to information that enables them to mitigate disease risk for their future child.
Read more about our guiding principles here.
Orchid wants to ensure that our products are accessible to all that could benefit; applications for financial assistance are available here. We are committed to expanding access to our technology to every couple that can benefit. We advocate for expanded access through insurance coverage and self-insured employers incorporating our technology into their plans. We are also building out resources for fertility and genetics education and a forum for broader conversation in the community.
Read more about our guiding principles here.