Choosing Wisely

The Choosing Wisely initiative, led by the American Board of Internal Medicine (ABIM) Foundation, emphasizes the importance of evidence-based medical decisions. Since its launch in 2012, the initiative identified over 700 tests and treatments that are overused or unnecessary. In genetics, careful test selection improves diagnostic accuracy while avoiding wasteful spending, which plays a role in supporting equitable access to genetic services. Listed below is a quick-reference guide of Choosing Wisely recommendations that provide a framework for clinicians to incorporate high-value genetic testing — balancing diagnostic utility with financial responsibility.

This focus on resource stewardship is especially important for patients with rare diseases, who often undergo a prolonged and costly diagnostic journey. A rare disease is “a disease, disorder, illness or condition that affects fewer than 200,000 Americans,” and together, around thirty million Americans are diagnosed with one (1). The diagnostic odyssey these patients face can span decades, leading to accumulating medical debt. Fortunately, advances in genetic testing offer an opportunity to shorten this diagnostic odyssey, improving both patient outcomes and healthcare efficiency. As rare patients experience significantly higher health-care utilization compared to common conditions, their cases account for nearly half of the U.S. national healthcare expense bill (2). RDPs face an average of $16,513 in direct healthcare costs and this is followed by $13,557 in informal costs and $4,579 in formal costs (3). In Canada, children suspected to have a rare disease face annual per-patient costs of C$511 for diagnostic testing alone, and annual consultations run an average of C$334 over time (4).  

Ultimately, it is important as providers to choose wisely regarding testing and care for this population. This reinforces the value of early genetic testing as an essential tool in providing high-value care. For example, in neonatal diabetes, genetic testing—though initially costly—has been shown to improve quality of life and reduce long-term healthcare expenses, saving an estimated $12,528 within the first ten years of diagnosis (5). Similarly, early diagnosis of neurodevelopmental diseases lowers treatment costs and provides children with earlier access to targeted interventions, ultimately improving their long-term health (6). 

Delays in diagnosis contribute to higher healthcare costs, often due to unnecessary procedures and ineffective treatments—in some cases spanning five or more years before diagnosis (7). This is not isolated to the United States. In Spain, 50.4% of patients with a confirmed diagnosis of rare diseases had a diagnostic delay exceeding one year, leading to higher monthly disease-related expenses (€300 on average) and a worse economic situation for families (8).  

In summary, delaying diagnosis of rare genetic diseases leads to significant healthcare costs due to increased treatment and care needs. Early and accurate diagnostic capabilities are vital for improving clinical outcomes and promoting sustainable healthcare spending. Use of the Choosing Wisely guidelines in case-based learning, clinical discussions and educational handouts can serve as a practical approach of promoting high-value genetics care.

Choosing Wisely Recommendations

American Academy of Family Physicians (AAFP):

• Don’t order a duplicate genetic test for an inherited condition unless there is uncertainty about the validity of the existing test result (9). 
• Don’t order MTHFR genetic testing for the risk assessment of hereditary thrombophilia (10). 

American College of Medical Genetics and Genomics (11)

The group recommends against ordering the following:

• Duplicate genetic tests for inherited conditions unless there is concern about the first test’s accuracy.
• APOE genetic testing to predict Alzheimer disease.
• MTHFR testing to assess risk for hereditary thrombophilia.
• HFE genetic testing for patients who don’t have iron overload or family history of HFE-associated hereditary hemochromatosis. 
• Exome or genome sequencing prior to getting informed consent that alerts patients of the possibility of incidental findings.

College of American Pathologists Recommendations (12)

• Constitutional genetic testing (CGT) should only be performed once in a patient’s lifetime except in very unusual circumstances. 

Canadian College of Medical Genetics Recommendations (13)

• Don’t use non-invasive prenatal detection of fetal aneuploidies by cell-free DNA as a diagnostic test. 
• Don’t make medical decisions based on results of direct to consumer genetic testing (DTC-GT) without a clear understanding of the limitations and validity of the test. 
• Don’t order a chromosome analysis by doing a karyotype for individuals with intellectual disability/developmental delay of unknown etiology. 
• Don’t order whole exome sequencing prior to genetic counseling. 
• Don’t order carrier testing in children. 
• Don’t order rapid or expedited testing if the results will not change management. 
• Don’t order broad panel or genomic testing when targeted testing is more appropriate due to specificity of the phenotype. 
• Don’t order a genome-based test when another genetic testing method is more appropriate. 
• Don’t routinely offer carrier screening when the chance of having an affected pregnancy is low. 
• Don’t order a sequencing test after a negative exome study. 
• Don’t automatically order metabolic testing for a child with isolated global developmental delay/intellectual disability. 
• Don’t proceed with genetic testing too early in a patient’s presentation.

Royal College of Pathologists Recommendations (14)

• Avoid unnecessary duplicate genetic testing for inherited variants

Human Genetics Society of Australasia Recommendations (15)

• Don’t undertake genetic testing when clinical diagnostic criteria exist and there are no reproductive or predictive testing implications.
• Don’t undertake sequential testing for heterogeneous genetic disorders when targeted next generation sequencing (NGS) is available
• Don’t undertake genetic testing for methylenetetrahydrofolate reductase (MTHFR), apolipoprotein E (APOE) and other such tests where the clinical utility for diagnostic purposes is extremely low
• Don’t undertake carrier state testing for rare recessive disorders where a partner has a family history, the couple is non-consanguineous and there are no common causative mutations.

Italian Society of Genetics (16)

• Don’t perform genetic testing for mutations analysis in the 5,10-Methylene TetraHydrofolate Reductase (MTHFR) gene
• Don’t perform genetic tests directly to consumers, purchased on websites, pharmacies, gyms, beauty institutions, without a doctor’s prescription.
• Don’t perform genetic tests for monogenic diseases without specific indication both in the physiological procreation or by assisted reproduction technology (ART).
• Don’t perform HLA genotyping in the presence of an established diagnosis of celiac disease or for screening purposes.
• Don’t perform screening tests of polymorphisms of factor V (Leiden) and Factor II (G20210A) in unselected patients, like all patients with only one episodes of venous thrombosis, in healthy subjects or in pregnant women with no specific anamnestic signs or before to start a treatment with oral contraceptives.
• Do not perform genetic testing for polymorphisms in genes involved in detoxification processes for the diagnosis of Multiple Chemical Sensitivity (MCS)
• Do not perform genetic testing for Y chromosome microdeletions as a screening test for all male patients with reproductive problems
• Do not include Glucose 6 Phosphate Dehydrogenase (G6PD) in the tests required for Medically Assisted Reproduction (MAP)
• Do not perform prenatal testing that can be performed on circulating fetal free fetal DNA (cfDNA) by non-invasive prenatal testing (NIPT) without first informing women about the limitations and accuracy of the different prenatal investigations that can be performed
• Do not perform test investigating genes associated with food metabolism and food intolerances (genetic testing for nutrition) to define a dietary path

Italian Society of Andrology and Sexual Medicine (17)

• Do not perform genetic tests and assessment of sperm DNA fragmentation in all male patients with sperm abnormalities.

American College of Rheumatology and the Canadian Rheumatology Association (18)

• Don’t order ANA as a screening test in patients without specific signs or symptoms of systemic lupus erythematosus (SLE) or another connective tissue disease (CTD).

Resources:

1. Wan EL, Elkaim Y, Gao W, et al. Zebras Among Us: Advocating for the 30 Million Americans Living with Rare Disease. Med Sci Educ 2023; 33: 1239–1242.
2. Navarrete-Opazo AA, Singh M, Tisdale A, et al. Can you hear us now? The impact of health-care utilization by rare disease patients in the United States. Genet Med 2021; 23: 2194–2201.
3. Sequeira AR, Mentzakis E, Archangelidi O, et al. The economic and health impact of rare diseases: A meta-analysis. Health Policy and Technology 2021; 10: 32–44.
4. Dragojlovic N, van Karnebeek CDM, Ghani A, et al. The cost trajectory of the diagnostic care pathway for children with suspected genetic disorders. Genet Med 2020; 22: 292–300.
5. Greeley SAW, John PM, Winn AN, et al. The Cost-Effectiveness of Personalized Genetic Medicine. Diabetes Care 2011; 34: 622–627.
6. Xie D, Duan R, Li C, et al. Study on the Economic Burden of Neurodevelopmental Diseases on Patients With Genetic Diagnosis. Front Public Health 2022; 10: 887796.
7. Hartley T, Lemire G, Kernohan KD, et al. New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases. Annu Rev Genomics Hum Genet 2020; 21: 351–372.
8. Gimenez-Lozano C, Páramo-Rodríguez L, Cavero-Carbonell C, et al. Rare Diseases: Needs and Impact for Patients and Families: A Cross-Sectional Study in the Valencian Region, Spain. Int J Environ Res Public Health 2022; 19: 10366.
9. Choosing Wisely Recommendations, https://www.aafp.org/pubs/afp/collections/choosing-wisely/281.html (accessed 5 February 2025).
10. Choosing Wisely Recommendations, https://www.aafp.org/pubs/afp/collections/choosing-wisely/283.html (accessed 5 February 2025).
11. Young K. Choosing Wisely: 5 Recommendations for Ordering Genetic Tests. NEJM Physician’s First Watch; 2015, https://www.jwatch.org/FW110419/2015/07/16/choosing-wisely-5-recommendations-ordering-genetic-tests (2015, accessed 5 February 2025).
12. Repetitive Constitutional Genetic Testing, https://documents.cap.org/documents/RepConstGeneticTest_ClinicianHandout.pdf (accessed 5 February 2025).
13. Five Things Physicians and Patients Should Question, https://choosingwiselycanada.org/wp-content/uploads/2017/05/Medical-genetics.pdf (accessed 5 February 2025).
14. Pathologists TRC of. Pathology-related Choosing Wisely recommendations, https://www.rcpath.org/profession/patient-safety-and-quality-improvement/patient-safety-resources/choosing-wisely/pathology-related-choosing-wisely-recommendations.html (accessed 5 February 2025).
15. Choosing Wisely Australia Recommendations, https://www.choosingwisely.org.au/recommendations?category=medicineBranch&medicineBranch=2751 (accessed 5 February 2025).
16. Choosing Wisely Italy, https://choosingwiselyitaly.org/en/societa/sigu-2/ (accessed 5 February 2025).
17. Choosing Wisely Italy, https://choosingwiselyitaly.org/en/raccomandazione-prof/do-not-perform-genetic-tests-and-assessment-of-sperm-dna-fragmentation-in-all-male-patients-with-sperm-abnormalities/ (accessed 5 February 2025).
18. Eleven Tests and Treatments to Question in Rheumatology, https://choosingwiselycanada.org/recommendation/rheumatology/ (accessed 5 February 2025).