Comprehensive genetic profiling offers the potential to evaluate a large number of genetic markers at a single time to identify cancer treatments that target specific biologic pathways. Some individual markers have established benefit in certain types of cancers; they are not addressed in this evidence review. Rather, this review focuses on "expanded" panels, which are defined as molecular panels that test a wide variety of genetic markers in cancers without regard for whether a specific targeted treatment has demonstrated benefit. This approach may result in treatment different from that usually selected for a patient based on the type and stage of cancer.

Chromosomal microarray (CMA) testing has been proposed for the detection of genetic imbalances in infants or children with characteristics of developmental delay/intellectual disability, autism spectrum disorder, and/or congenital anomalies. CMA testing increases the diagnostic yield over karyotyping in children with the aforementioned characteristics, and CMA testing may impact clinical management decisions. Next-generation sequencing panel testing allows for the simultaneous analysis of a large number of genes and, in patients with normal CMA testing, next-generation testing has been proposed as a way to identify single-gene causes of syndromes that have autism as a significant clinical feature.

Genetic panel testing offers potential advantages and disadvantages compared with direct sequence analysis. This conceptual framework outlines a structure for evaluating the utility of genetic panels, by classifying them into clinically relevant categories and developing criteria for evaluating panels in each category. Genetic panels using next-generation technology or chromosomal microarray analysis are available for many clinical conditions. The major advantage of panels is the ability to analyze many genes simultaneously, potentially improving the breadth and efficiency of the genetic workup. A potential disadvantage of panels is that they provide a large of amount of ancillary information whose significance may be uncertain. Limited published evidence has reported that the analytic validity of panels approaches that of direct sequencing. The clinical validity and clinical utility of panels are condition-specific. The clinical validity of panels will reflect the clinical validity of the underlying individual variants. The clinical utility of panels will depend on the context in which they are used, ie, whether the advantages of panel testing outweigh the disadvantages for the specific condition under consideration. Panels can be classified into categories based on their intended use and composition. For each category of panels, specific criteria can be used to evaluate medical necessity. When all criteria for a given category are met, that panel may be considered medically necessary.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of several types of tumors. The syndrome is caused by germline pathogenic variants in the TP53 gene. Testing for LFS pathogenic variants may be useful in confirming the diagnosis of LFS and/or evaluating genetic status in asymptomatic relatives of an index case.

Expression levels of various genes in circulating white blood cells or whole blood samples have been reported to discriminate between cases of obstructive coronary artery disease and healthy controls. Multiplex gene expression testing has been combined with other risk factors to estimate the likelihood of obstructive coronary artery disease in patients who present with stable ischemic heart disease. These tests have the potential to improve the accuracy of predicting coronary artery disease. A commercially available test, Corus CAD, has been developed for this purpose without diabetes or inflammatory conditions. For individuals who have suspected stable ischemic heart disease without diabetes or inflammatory conditions who receive gene expression testing, the evidence includes retrospective case-control and prospective cohort studies. Relevant outcomes are overall survival, disease-specific survival, test validity, change in disease status, morbid events, and resource utilization. The diagnostic pathway for coronary artery disease includes information from medical history, along with age and sex, stress testing, and imaging. Newer noninvasive methods are being tested, such as gene expression testing. It is not clear how the Corus CAD gene expression test fits in the current diagnostic pathway and how results would be used to change current guideline-based risk stratification before and/or after other noninvasive testing. Results of 2 validation studies (Personalized Risk Evaluation and Diagnosis In the Coronary Tree [PREDICT], Coronary Obstruction Detection by Molecular Personalized Gene Expression [COMPASS]) have reported that the test may improve coronary artery disease prediction beyond the Diamond-Forrester prediction model. In the COMPASS study, the sensitivity and negative predictive value of the Corus CAD score in diagnosing obstructive coronary artery disease was superior to myocardial perfusion imaging in patients referred for myocardial perfusion imaging testing. However, in that study, the reported sensitivity of myocardial perfusion imaging was considerably lower than that generally reported in the literature. Neither PREDICT nor COMPASS used the guideline definition of obstructive coronary artery disease as the reference standard and had relatively few patients at intermediate risk based on clinical prediction rules. The sensitivity and negative predictive value of clinical models were not reported. An analysis of a cohort from the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) trial including patients with an intermediate pretest probability of obstructive coronary artery disease confirmed a high, negative predictive value for the Corus CAD score. The test also has been shown to have some predictive ability of future revascularization; too few major cardiac events have been observed during the limited duration of follow-up to assess predictive ability for that outcome. Evidence for the Corus CAD score has not directly demonstrated that the test is clinically useful and a chain of evidence cannot be constructed to support its utility. The evidence is insufficient to determine the effects of the technology on health outcomes.

Genetic testing of adults with suspected lactase insufficiency is proposed as an alternative to current diagnostic practices, which include hydrogen breath test, lactose tolerance blood test, and intestinal biopsy.

Chromosomal microarray (CMA) testing of fetal tissue or placental tissue derived from the fetal genotype has been proposed as a technique to evaluate the cause of isolated and recurrent early pregnancy loss (miscarriages) and later pregnancy loss (intrauterine fetal demise [IUFD]). The evaluation of both recurrent and isolated miscarriages and IUFD may involve genetic testing of the products of conception. Such testing has typically been carried out through cell culture and karyotyping of cells in metaphase. However, the analysis of fetal or placental tissue has been inhibited by the following limitations: the need for fresh tissue, the potential for cell culture failure, and the potential for maternal cell contamination.

Hearing loss is a common birth defect. Approximately 1 in 500 newborns in developed countries is affected by bilateral, permanent hearing loss of moderate or greater severity (≥40 decibels). Syndromic hearing loss refers to hearing loss associated with other medical or physical findings, including visible abnormalities of the external ear. Because syndromic hearing loss occurs as part of a syndrome of multiple clinical manifestations, it is often recognized more readily as hereditary. Nonsyndromic hearing loss is defined as hearing loss not associated with other physical signs or symptoms. Nonsyndromic hearing loss accounts for 70% to 80% of genetically determined deafness, and it is more difficult to determine whether the etiology is hereditary or acquired.

The PTEN hamartoma tumor syndrome (PHTS) includes several syndromes with heterogeneous clinical symptoms, which may place individuals at an increased risk for the development of certain types of cancer. Genetic testing for PTEN can confirm a diagnosis of PHTS.

Gene expression profile (GEP) and circulating tumor DNA (ctDNA) tests have been developed for use as prognostic markers of stage II or III colon cancer to help identify patients who are at high-risk for recurrent disease and could be candidates for adjuvant chemotherapy.

Rhesus D (RhD)-negative women who are exposed to RhD-positive red blood cells can develop anti-RhD antibodies, which can cross the placenta and cause fetal anemia. If undiagnosed and untreated, alloimmunization can cause significant perinatal morbidity and mortality. Determining the RhD status of the fetus may guide subsequent management of the pregnancy. Hence, the use of cell-free fetal DNA (cffDNA) in maternal blood has been proposed as a noninvasive method to determine fetal RHD genotype.

Rett syndrome (RTT), a neurodevelopmental disorder, is usually caused by pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene. Genetic testing is available to determine whether a pathogenic variant exists in RTT-associated genes (eg, MECP2, FOXG1, or CDLK5) in an individual with clinical features of RTT or an individual's family member.

Inherited thrombophilias are a group of disorders that predispose individuals to thrombosis. Genetic testing is available for some of these disorders and could assist in the diagnosis and/or management of patients with thrombosis. For example, testing is available for types of inherited thrombophilia, including variants in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, the factor V gene (factor V Leiden [FVL] variant), and the prothrombin (factor II) gene.

The identification of specific, targetable oncogenic “driver mutations” in a subset of melanomas and gliomas has resulted in a reclassification of solid tumors to include molecular subtypes that may direct targeted therapy depending on the presence of specific variants. B-raf proto-oncogene, serine/threonine kinase (BRAF) and mitogen-activated protein kinase (MEK) inhibitors are drugs designed to target a somatic variant in the BRAF gene. BRAF and MEK inhibitors were originally developed for patients with advanced melanoma. BRAF encodes a kinase component in the rapidly accelerated fibrosarcoma (RAF)-MEK-extracellular signal-regulated kinase (ERK) signal transduction phosphorylation cascade. Variants in BRAF cause constitutive kinase activity, which is believed to promote oncogenic proliferation. Direct and specific inhibition of the mutated kinase has been shown to retard tumor growth significantly and may improve patient survival. The neurotrophic receptor tyrosine kinase (NTRK) gene fusions are uncommon kinase fusion events that drive tumorigenesis in a small fraction of solid tumors, regardless of tissue type.1, The tropomyosin receptor kinases (TRK) proteins A, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 respectively. In healthy tissue, the TRK pathway is involved in the development and functioning of the nervous system as well as cell survival. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that are oncogenic, promoting tumor cell proliferation and their survival. Larotrectinib and entrectinib is a kinase inhibitor of TRK A, B, and C protein. Entrectinib additionally inhibits 2 other kinases: anaplastic lymphoma kinase and proto-oncogene tyrosine-protein kinase. The presence of NTRK gene fusions can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry.2, Mutations in isocitrate dehydrogenase-1 (IDH1) or -2 (IDH2) genes lead to accumulation of the proto-oncogenic metabolite D-2-hydroxyglutarate, disrupting gene expression and cellular differentiation. WHO grade 2 and 3 astrocytomas and oligodendrogliomas are defined by IDH mutations, distinguishing lower-grade gliomas from glioblastomas. IDH1 and IDH2 mutations are generally associated with a favorable prognosis, and have been important biomarkers for stratification in clinical trials. IDH mutations are detected in over 50% of gliomas in patients aged 55 or older.3,

Variants in the NOTCH3 gene have been causally associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Genetic testing is available to determine if pathogenic variants exist in the NOTCH3 gene for patients with suspected CADASIL and their family members.

Over half of patients with non-small-cell lung cancer (NSCLC) present with advanced and therefore incurable disease. Treatment in this setting has been with platinum-based chemotherapy. The identification of specific, targetable oncogenic “driver mutations” in a subset of NSCLCs has resulted in a reclassification of lung tumors to include molecular subtypes that may direct targeted therapy or immunotherapy depending on the presence of specific variants.

The cytochrome P450 (CYP450) family is involved in the metabolism of many currently administered drugs, and genetic variants in CYP450 are associated with altered metabolism of many drugs. Testing for CYP450 variants may assist in selecting and dosing drugs affected by these genetic variants.

The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC). EGFR-targeted therapy combined with monoclonal antibodies cetuximab and panitumumab has shown a clear survival benefit in patients with metastatic CRC. However, this benefit depends on a lack of variants in certain genes in the signaling pathway downstream from the EGFR. It has been hypothesized that knowledge of tumor cell KRAS, NRAS, BRAF variant status might be used to predict nonresponse to anti-EGFR monoclonal antibody therapy. NTRK gene fusions, which are rare kinase fusion events, are a potential therapeutic target for CRC patients who may benefit from tropomysosin receptor kinase (TRK) inhibitor therapy. RET gene fusions, which are also rare, are a potential therapeutic target for CRC patients who may benefit from tyrosine kinase inhibitor therapy. More recently, human epidermal growth factor receptor 2 (HER2) testing to select patients for targeted therapy has been proposed. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA or circulating tumor cell testing (also known as a liquid biopsy) is proposed as a non-invasive alternative.

A variety of serum biomarkers have been studied for their association with ovarian cancer. Of particular interest have been tests that integrate results from multiple analytes into a risk score to predict the presence of disease. Three tests based on this principle, OVA1, Overa (the second-generation OVA1 test), and the Risk of Ovarian Malignancy Algorithm (ROMA) have been cleared by the U.S. Food and Drug Administration. The intended use of OVA1 and Overa is as an aid to further assess whether malignancy is present in an individual with an ovarian adnexal mass who has not yet been referred to an oncologist, even when the physician’s independent clinical and radiologic evaluation does not indicate malignancy. The intended use of ROMA is as an aid, in conjunction with clinical assessment, to assess whether a premenopausal or a postmenopausal woman who presents with an ovarian adnexal mass and has not yet been referred to an oncologist is at a high or low likelihood of finding malignancy on surgery.

Familial hypertrophic cardiomyopathy is an inherited condition caused by a disease associated variant in 1 or more of the cardiac sarcomere genes. Hypertrophic cardiomyopathy is associated with numerous cardiac abnormalities, the most serious of which is sudden cardiac death. Genetic testing for hypertrophic cardiomyopathy associated variants is available through a number of commercial laboratories.

Clinical assessment and noninvasive imaging of chronic heart failure can be limited in accurately diagnosing patients with heart failure because symptoms and signs can poorly correlate with objective methods of assessing cardiac dysfunction. For management of heart failure, clinical signs and symptoms (eg, shortness of breath) are relatively crude markers of decompensation and occur late in the course of an exacerbation. Thus, circulating biomarkers have potential benefit in heart failure diagnosis and management. In transplant recipients, despite the progress in immunosuppressant therapy, the risk of rejection remains. Diagnosis of allograft rejection continues to rely on clinical monitoring and histologic confirmation by tissue biopsy. However, due to limitations of tissue biopsy, including a high degree of interobserver variability in the grading of results and its potential complications, less invasive alternatives have been investigated. Several laboratory-tested biomarkers of transplant rejection have been evaluated and are commercially available for use. The laboratory tests for heart transplant rejection currently evaluated in this policy include the Presage® ST2 Assay kit, which measures the soluble suppression of tumorigenicity-2 (sST2) protein biomarker; ; the Heartsbreath test, which measures breath markers of oxidative stress; the AlloSure, Prospera Heart and myTAIHEART tests for assessment of donor-derived cell-free DNA (dd-cfDNA); the AlloMap test, which uses gene expression profiling (GEP); and the HeartCare test, which combines AlloMap GEP testing with the AlloSure test. Also included in this policy are the AlloSure and Prospera dd-cfDNA tests for assessment of renal and lung transplant rejection.

Data suggest that cytologic screening for cervical cancer reduces the incidence of cervical cancer by up to 50%. Several technologies have been investigated for their role in detecting cancerous and precancerous cervical lesions. Evidence firmly supports the use of HPV testing for both initial screening in women older than age 30 and in triage of ASCUS results for all women. The use of automated slide reading systems is supported by a small body of evidence that the systems may increase sensitivity <a id="

Tests that integrate microscopic analysis with molecular tissue analysis are generally called topographic genotyping. Interpace Diagnostics offers 2 such tests that use the PathFinderTG® platform (PancraGEN® ). These molecular tests are intended to be used adjunctively when a definitive pathologic diagnosis cannot be made, because of the inadequate specimen or equivocal histologic or cytologic findings, to inform appropriate surveillance or surgical strategies.

Systems pathology, an approach that combines cellular and biologic features to standard clinical parameters, such as age, clinical or pathologic stage, grade, percent of cancer on biopsy cores, and prostate-specific antigen (PSA) or its derivatives, is proposed as a way to estimate the probability of disease progression or recurrence, either before or after prostatectomy.

Many cancers appear to have a better prognosis if diagnosed early in their natural history. This has led to efforts to detect preclinical cancers in asymptomatic individuals through screening. Cancer screening tests such as ‘liquid biopsies’ that are minimally invasive and can simultaneously detect multiple types of cancer have been called multicancer early detection (MCED) tests.

Improved accuracy of the identification of pregnant people at risk of preeclampsia and spontaneous preterm birth has the potential to reduce maternal and perinatal morbidity and mortality. Assessment of historical risk and clinical factors represents the traditional approach to diagnosis and planning interventions. Maternal serum biomarker testing is proposed as an adjunct to standard screening to identify pregnant people at risk of preeclampsia and spontaneous preterm birth.

The Antigen Leukocyte Antibody Test (ALCAT) is intended to diagnose intolerance to foods and other environmental agents. It is a blood test that assesses the response of leukocytes and platelets to a panel of foods and/or other environmental agents by measuring the change in size and number of cells following exposure to a specific agent.

Calprotectin is a calcium- and zinc-binding protein that is a potential marker of intestinal inflammation. Fecal calprotectin testing is proposed as a noninvasive means to diagnose inflammatory bowel disease (IBD). Other potential uses are to evaluate treatment response for individuals with IBD and as a marker of relapse.

Individuals in pain management programs and substance use disorder treatment may misuse prescribed opioids and/or may use nonprescribed drugs. Thus, these individuals are often assessed before treatment and monitored while receiving treatment. Drug testing can be part of this monitoring strategy; it is most often used as part of a multifaceted intervention that includes other components, such as participant contracts.

Vitamin D, also known as calciferol, is a fat-soluble vitamin that has a variety of physiologic effects, most prominently in calcium homeostasis and bone metabolism. In addition to the role it plays in bone metabolism, other physiologic effects include inhibition of smooth muscle proliferation, regulation of the renin-angiotensin system, a decrease in coagulation, and a decrease in inflammatory markers.

Multimarker nutritional panel testing is proposed for patients with certain chronic conditions (eg, mood disorders, fibromyalgia, unexplained fatigue) as well as for healthy individuals seeking to optimize health and/or fitness.

Bacterial vaginosis (BV) is a common medical condition resulting from an imbalance in the normal vaginal flora. Although the identification of Gardnerella vaginalis has traditionally been associated with BV, there is no single etiologic agent. Most cases are asymptomatic, and most symptomatic cases can be diagnosed using clinical and microscopic evaluation. Multitarget polymerase chain reaction (PCR) testing is proposed as an alternative to currently available laboratory tests to diagnose BV. This test may improve outcomes if it is a more accurate and reliable method to diagnose BV.

Commercial laboratories offer panels of tests evaluating intracellular levels of micronutrients (essential vitamins and minerals). Potential uses of these tests include screening for nutritional deficiencies in healthy individuals or those with chronic disease and aiding in the diagnosis of disease in individuals with nonspecific symptoms.

Novel assays that quantitatively measure total human epidermal growth factor receptor 2 (HER2) protein expression and homodimers have been developed to improve the accuracy and consistency of HER2 testing. However, the HERmark Breast Cancer Assay, the sole assay included in this review, was discontinued by the manufacturer in September 2020 (Monogram Biosciences, oral communication, November 2020).

Intestinal dysbiosis may be defined as a state of disordered microbial ecology that is believed to cause disease. Laboratory analysis of fecal samples is proposed as a method of identifying individuals with intestinal dysbiosis and other gastrointestinal disorders.

Bone turnover markers are biochemical markers of either bone formation or bone resorption. Commercially available tests are available to assess some of these markers in urine and/or serum by high-performance liquid chromatography or immunoassay. Assessment of bone turnover markers is proposed to supplement bone mineral density measurement in the diagnosis of osteoporosis and to aid in treatment decisions. Bone turnover markers could also potentially be used to evaluate treatment effectiveness before changes in bone mineral density can be observed.

Biochemical changes associated with the pathophysiology of Alzheimer disease (AD) are being evaluated to aid in the diagnosis of AD. This includes the potential use of biomarkers, such as amyloid beta peptide 1-42 and total or phosphorylated tau protein, in cerebrospinal fluid (CSF) and urine. Additionally, the potential correlation between CSF biomarkers and positron emission tomography (PET) amyloid scans may assist in selecting appropriate patients for the initiation or discontinuation of amyloid beta plaque targeted therapy.

Careful monitoring of lifelong immunosuppression is required to ensure the long-term viability of solid organ allografts without incurring an increased risk of infection. The monitoring of immunosuppression parameters attempts to balance the dual risks of rejection and infection. It is proposed that individual immune profiles, such as an immune cell function assay, will help assess the immune function of the transplant recipient and individualize immunosuppressive therapy.

HIV tropism testing can determine the predominant coreceptor protein used by HIV to infect target cells. Tropism testing can help select patients for treatment with HIV coreceptor antagonists (eg, maraviroc), which block specific coreceptor proteins. For individuals who have HIV infection who are being considered for HIV coreceptor antagonist therapy who receive HIV tropism testing, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are overall survival, disease-specific survival, morbid events, quality of life, hospitalizations, medication use, and treatment-related morbidity. RCTs on treatment-naive and treatment-experienced HIV-infected patients have provided evidence that selection of candidates for HIV coreceptor antagonist therapy using HIV tropism testing results in higher rates of treatment success compared with HIV coreceptor antagonist therapy without HIV tropism testing. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. For individuals with HIV infection receiving HIV coreceptor antagonist therapy or who have failed coreceptor antagonist therapy who receive HIV tropism testing, the evidence includes post hoc analysis of RCTs and observational studies. Relevant outcomes are overall survival, disease-specific survival, morbid events, quality of life, hospitalizations, medication use, and treatment-related mortality and morbidity. Current evidence does not indicate improved outcomes with additional tropism monitoring during treatment. The evidence is insufficient to determine the effects of the technology on health outcomes. For individuals with HIV infection who are undergoing tests to predict disease progression who receive HIV tropism testing, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, morbid events, quality of life, hospitalizations, and medication use. Current evidence is inconsistent in as relates to whether HIV tropism testing independently predicts disease progression among HIV-infected patients. The evidence is insufficient to determine the effects of the technology on health outcomes <a id="

Severe infection and sepsis are frequent causes of morbidity and mortality in intensive care units. Infection and sepsis are accompanied by clinical signs and changes in laboratory analysis, as well as changes in body temperature, leukocytosis and tachycardia. However, these signs and symptoms of systemic inflammation (SIRS) may have an infectious or non-infectious etiology. They are not specific or sensitive to sepsis. A similar inflammatory response can be seen in patients with pancreatitis, severe trauma and burns without infectious complications. Sometimes it is difficult to distinguish patients with systemic infection, organ dysfunction and "shock" from other patients with the same clinical symptoms and laboratory findings that do not have infection. Bacteriological evidence of the infection may not develop at the same time as the clinical symptoms of sepsis. Positive bacteriological tests may result from contamination and similarly negative tests do not necessarily exclude sepsis. Since this symptomatology and laboratory analysis are not sufficiently sensitive or specific, an initial marker that identifies the infection as a cause of the systemic inflammatory response is necessary. Recently the measure of procalcitonin has been proposed as that marker. The Procalcitonin is normally produced in thyroid C cells and is the precursor of calcitonin. A specific protease converts procalcitonin to calcitonin , katacalcin and a terminal N residue. Under normal conditions all the Procalcitonin is converted and nothing reaches the bloodstream, therefore, procalcitonin levels are undetectable (<0.1ng / ml) in a healthy person. During a severe infection with systemic manifestations the levels can increase up to 100 ng / ml. These increases in procalcitonin do not produce an increase in calcitonin because the half-life of this is 10 minutes while that of procalcitonin is 25-30 hours in the serum.In the presence of severe and generalized bacterial, parasitic or mycotic infections with systemic manifestations, and procalcitonin levels increase. In severe viral infections or inflammatory reactions of non-infectious origin, procalcitonin does not increase or shows only a moderate increase. Procalcitonin was approved by the FDA in January 2005. It has not been evaluated by the Technology Assessment Center (TEC) of the BCBS Association. <a id="

Homocysteine is an amino acid that has been evaluated as a potential marker of cardiovascular disease (CVD) and as a potential risk marker for people with CVD and thrombotic disorders; the presence of this amino acid raises one’s risk of developing a blood clot. The association between homocysteine-lowering interventions and the risk of CVD or thrombotic events has been examined.

Epidemiologic studies have reported that subjects who eat a diet high in fish have a reduced risk of sudden cardiac death. Fish are rich in long-chain omega-3 fatty acids, and it has been hypothesized that these fatty acids may be responsible for the beneficial effect. Long-chain omega-3 fatty acids may be detected in the red cell membrane using gas chromatography. It has been suggested this measurement may be clinical useful as a cardiac risk factor for sudden cardiac death. <a id="

The prognosis of cancer patients is often determined by the occurrence of metastatic disease. Studies have suggested that the presence of circulating tumor cells (CTCs) in patients with metastatic carcinoma is associated with shortened survival. The detection of CTCs might be useful for assessing prognosis and guiding cancer therapy. While studies have shown that the level of CTCs is associated with the presence of metastatic disease and prognosis, the prospective use of this information to impact care has not been demonstrated. Given that insufficient evidence is available to evaluate the impact on patient management or health outcomes and additional remaining questions (eg, the optimal cutoff to use for various conditions) the assessment of CTCs is considered investigational.

While multiple pharmacologic therapies are available for the management of acute and chronic pain, there is a high degree of heterogeneity in pain response, particularly in the management of chronic pain, and in adverse events. Testing for genetic variants that are relevant to pharmacokinetics or pharmacodynamics of analgesics may assist in selecting and dosing drugs affected by these genetic variants.

Serum antibodies to polysaccharide-containing molecules, called glycans, and other serum biomarkers are potential biomarker tests for the diagnosis and prognosis of multiple sclerosis (MS). MS is diagnosed according to criteria that incorporate clinical symptoms and magnetic resonance imaging and cerebrospinal fluid findings. Currently, there is no biomarker available to inform diagnosis or prognosis. A serum biomarker is particularly desirable because of ease of repeat measurements. For individuals who have signs and/or symptoms of MS who receive serum biomarker tests for MS, the evidence includes cross-sectional studies of diagnostic accuracy and cohort studies. Relevant outcomes are test accuracy and validity, other test performance measures, symptoms, functional outcomes, health status measures, and quality of life. Antibodies to glycan molecules are thought to impair immune function. They include antibodies to 1 (glucose[α1,4]glucose[α] [GAGA4]) or several (GAGA2, -3, -4, and – 6) glycan molecules. The gMS Dx and gMS Pro EDSS tests may aid in the diagnosis and prognosis in MS, respectively. Tests for serum levels of other potential MS biomarkers, including but not limited to apoptosis-related molecules, intercellular adhesion molecules, and myelin peptides, have also been described. Current evidence for these other biomarkers makes it difficult to assess their utility in diagnosis and prognosis. The evidence is insufficient to determine the effects of the technology on health outcomes. <a id="

The diagnosis of bladder cancer is generally made by cystoscopy and biopsy. Bladder cancer has a very high frequency of recurrence and therefore follow-up cystoscopy, along with urine cytology, is done periodically to identify recurrence early. Urine biomarkers that might be used to supplement or supplant these tests have been actively investigated. Urinary biomarkers have also been suggested to have utility in identifying colonic polyps.

Somatic (acquired) genetic variants in JAK2, MPL, and CALR genes have been implicated as the underlying molecular genetic drivers for the pathogenesis of myeloproliferative neoplasms (MPN). This evidence review addresses the use of genetic testing for JAK2, MPL, and CALR genes for diagnosis, prognosis, and treatment selection of individuals with MPN.

Human epididymis protein 4 (HE4) is a novel biomarker that has been cleared by the U.S. Food and Drug Administration for monitoring individuals with epithelial ovarian cancer. HE4 is proposed as a replacement for or a complement to cancer antigen 125 (CA 125) for monitoring disease progression and recurrence. HE4 has also been proposed as a test to evaluate women with ovarian masses and to screen for ovarian cancer in asymptomatic women.

Noninvasive techniques to monitor liver fibrosis are being investigated as alternatives to liver biopsy in patients with chronic liver disease. There are 2 options for noninvasive monitoring: (1) multianalyte serum assays with algorithmic analysis of either direct or indirect biomarkers; and (2) specialized radiologic methods, including magnetic resonance elastography, multiparametric magnetic resonance imaging (MRI), transient elastography, acoustic radiation force impulse imaging, and real-time transient elastography.

Nucleic acid probes are available for the identification of a wide variety of microorganisms. Nucleic acid probes can also be used to quantitate the number of microorganisms present. This technology offers advantages over standard techniques when rapid identification is clinically important, microbial identification using standard culture is difficult or impossible, and/or treatment decisions are based on quantitative results.

Several invasive and non-invasive tests are available for the detection of Helicobacter pylori infection in patients with peptic ulcer disease for diagnosis and test-of-cure. Other circumstances that may warrant testing include a history of peptic ulcer disease and MALT lymphoma. <a id="

In vitro chemoresistance and chemosensitivity assays have been developed to provide information about the characteristics of an individual patient's malignancy to predict potential responsiveness of their cancer to specific drugs. Oncologists may sometimes use these assays to select treatment regimens for a patient. Several assays have been developed that differ concerning the processing of biologic samples and detection methods. However, all involve similar principles and share protocol components including (1) isolation of cells and establishment in an in vitro medium (sometimes in soft agar); (2) incubation of the cells with various drugs; (3) assessment of cell survival; and (4) interpretation of the result.

Extensive evidence has established that anti-CCP has a moderately high sensitivity, a high specificity, and is a strong predictor of future erosive arthritis. The test is useful in confirming the diagnosis of RA in patients with early disease, especially when the criteria for a diagnosis of RA are not met by other clinical or laboratory measures. Early identification of patients with RA is important, since early treatment with DMARDs can prevent progression of destructive arthritis and improve functional status. The use of antiCCP for diagnosing RA has been incorporated into the latest diagnostic criteria for RA developed by the American College of Rheumatology (ACR). The evidence suggests that anti-CCP is not useful as a measure of disease activity and/or response to treatment. As a result, the use of anti-CCP is considered medically necessary for the diagnosis of RA and is considered investigational for monitoring disease activity in RA. <a id="

Surgical blood conservation techniques are used to reduce patient exposure to allogeneic blood during and after surgery. Techniques include preoperative autologous donation, intraoperative hemodilution, and blood salvage (also called cell salvage) during surgery. <a id="

Acupuncture is the practice of piercing the skin with needles at specific body sites to induce anesthesia, to relieve pain to alleviate withdrawal symptoms of substance abusers, or to treat various non-painful disorders. The placement of needles into the skin is dictated by the location of meridians. These meridians are thought to mark patterns of energy flow throughout the human body. Acupuncture has 4 components—the acupuncture needle(s), the target location defined by traditional Chinese medicine, the depth of insertion, and the stimulation of the inserted needle. Acupuncture may be performed with or without electrical stimulation. Acupuncture is a traditional form of Chinese medical treatment that has been practiced for over 3,000 years. The U.S. Food and Drug Administration (FDA) has cleared acupuncture needles for marketing. The needles used in acupuncture, when intended for general use in “the performance of acupuncture,” have been classified by the FDA as Class II devices (The Gray Sheet, April 8, 1996). <a id="

A Social worker is a person trained to help people manage, prevent or cope with everyday problems. They are employed in a variety of settings, mostly child welfare and human services, schools, or healtcare agencies providers. A bachelor's or master's degree is required in all settings, and it should be accredited by the Council on Social Work Education. A license is required to practice, and others requirements may apply depending on the state. A Clinical Social Worker requires a master's degree, supervised clinical experience, and a license from the Council of Social Workers Professionals of Puerto Rico. <a id="

The osteopath is a health professional whose studies are equivalent to a doctorate. His training emphasizes the interrelationship of the body's nerves, muscles, bones, and organs. The osteopathic exam covers everything that is concerned and covered in the ordinary medical exam. However, given the emphasis the osteopath places on the musculoskeletal system, it includes more intensively a structural examination. In this part of the physical examination the osteopath assesses posture, spine, and balance. Use your hands to feel the back, legs, arms, joints, muscles, tendons, and ligaments to determine their condition. <a id="

A Clinical Psychologist refers to a person or health professional who holds a master's or doctoral degree in psychology from an accredited university, college, or center. Practice of psychology includes diagnosis, the application of principles, methods, and procedures to analyze and change human behavior. These principles include those related to thinking, emotions, perceptions, interpersonal relationships, and learning. The method may include interviews, consultations, and the performance and interpretation of psychological tests (tests of mental abilities, motivation, aptitudes, and characteristics of the individual's psychological profile). The Clinical Psychologist must consult with the referring psychiatrist or primary care physician, except when the patient requests that the consultation with the primary care psychiatrist or physician not be carried out. This consultation will not be billed but is required. To participate in the plan, the following requirements must be met: • A doctoral degree in clinical psychology from an entity approved by the Council on Postsecondary Accreditation. You may not bill for psychotherapy treatments described in the following codes: 90832, 90834, 90837, 90839, 90840, 90846, 90847, 90849, or 90853. • A State Board license to practice clinical psychology. • Two years of experience, one of which must be postdoctoral work. <a id="

The primary mode of chiropractic treatment is manual or instrument-assisted manipulation or adjustment. Chiropractic manipulation is the application of a controlled, specific, and gentle force to re-establish normal articular function. The objective of the manipulation is to restore the normal mobility and range of motion within the joint. <a id="

A blood glucose monitor (glucometer) is a portable, battery-operated device used to determine the blood glucose level by exposing a reagent strip to a small blood sample. The patient uses a disposable lancet, draws a drop of blood, places it on a reagent strip, and inserts it into the monitor, which provides the patient with a direct readout of the blood glucose level. There is also a blood glucose monitor designed specifically for use by patients who are visually impaired. These monitors differ from the standard blood glucose monitor; they have voice synthesizers, timers, and specific placement of supplies to enable the patient to use the equipment without assistance. A disposable test system is available with the meter attached to the cap of the vial of reagent strips that no longer requires calibration of the meter. This policy conforms to the Charter Regulations No.: CN-2016-204-AS and the administrative order No.: 361 (signed by Dr. Ana Rius Armendariz, Secretary of health. <a id="

Telemedicine is the remote exchange of medical information through secure electronic communication to support diagnosis, consultation, treatment, and monitoring. “Telemedicine” and “telehealth” are often used interchangeably, although telehealth encompasses a broader range of services (eg, videoconferencing, image transmission, remote monitoring). Its main value lies in expanding access to care for medically and socially vulnerable populations, patients in rural or underserved areas, and during circumstances that make in-person consultation impractical (eg, pandemics, mobility limitations). Evidence supports its effectiveness in improving patient satisfaction, continuity of care, and management of chronic and acute non–life-threatening conditions. <a id="

A clinical trial is a research study that is used in the medical field to find new avenues to improve health. Clinical trials can: • Try new treatments for certain conditions or diseases to determine if they are better than the current one • Try treatments or change lifestyles to see if they prevent or lower the chance of acquiring certain diseases • Develop new tests for the diagnosis of diseases. <a id="

Ocriplasmin is a recombinant truncated form of human plasmin, a proteolytic enzyme that breaks down protein components at the vitreoretinal interface in the eye, used for symptomatic vitreomacular adhesion and vitreomacular traction. Ocriplasmin is injected into the affected eye (intravitreal) as a single dose and can induce vitreous liquefaction and separation from the retina.

Glaucoma surgery is intended to reduce intraocular pressure when the target intraocular pressure cannot be reached with medications. Due to complications with established surgical approaches (eg, trabeculectomy), alternative surgical treatments (eg, transluminal dilation by viscocanalostomy or canaloplasty) are being evaluated for individuals with glaucoma.

Corneal collagen cross-linking is a photochemical procedure approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive keratoconus and corneal ectasia following refractive surgery. Keratoconus is a dystrophy of the cornea characterized by progressive deformation (steepening) of the cornea, while corneal ectasia is keratoconus that occurs following refractive surgery. Both conditions can lead to functional loss of vision and need for corneal transplantation.

Retinopathy telescreening and risk assessment with digital imaging systems are proposed as an alternative to conventional dilated fundus examination in diabetic individuals. Digital imaging systems use a digital fundus camera to acquire a series of standard field color images and/or monochromatic images of the retina of each eye. Captured digital images may be transmitted via the Internet to a remote center for interpretation, storage, and subsequent comparison.

Orthoptic training refers to techniques designed to correct accommodative and convergence insufficiency (or convergence dysfunction). Regimens may include push-up exercises using an accommodative target of letters, numbers, or pictures; push-up exercises with additional base-out prisms; jump-to-near convergence exercises; stereogram convergence exercises; and/or recession from a target. In addition to its use to treat convergence insufficiency, orthoptic training has been investigated for treating attention deficit disorders, dyslexia, and dysphasia.

A keratoprosthesis, consisting of a central optic held in a cylindrical frame, is an artificial cornea intended to restore vision to patients with severe bilateral corneal disease for whom a corneal transplant is not an option. The keratoprosthesis replaces the cornea that has been removed and is held in place by the surrounding tissue. Various biologic materials are being investigated to improve integration of the prosthetic into the eye.

Glaucoma surgery is intended to reduce intraocular pressure (IOP) when the target IOP cannot be reached using medications. Due to complications with established surgical approaches (eg, trabeculectomy), a variety of shunts and stents are being evaluated as alternative surgical treatments for patients with inadequately controlled glaucoma. Microstents are also being evaluated in patients with mild-to-moderate open-angle glaucoma (OAG) currently treated with ocular hypotensive medication.

Thermal pulsation is a treatment option for meibomian gland dysfunction. Meibomian gland dysfunction is recognized as the major cause of dry eye syndrome. Thermal pulsation applies heat to the palpebral surfaces of the upper and lower eyelids directly over the meibomian glands, while simultaneously applying graded pulsatile pressure to the outer eyelid surfaces, thereby expressing the meibomian glands.

Angiogenesis inhibitors (eg, ranibizumab, bevacizumab, pegaptanib, aflibercept) are being evaluated for the treatment of disorders of choroidal circulation. Ophthalmic disorders affecting the choroidal circulation include age-related macular degeneration (AMD), central serous chorioretinopathy (CSC), pathologic myopia, presumed ocular histoplasmosis syndrome, angioid streaks, idiopathic choroidal neovascularization (CNV), uveitis, choroidal rupture or trauma, and chorioretinal scars.The available literature from randomized controlled trials supports the use of antivascular endothelial growth factor (anti-VEGF) therapies (ranibizumab, bevacizumab, pegaptanib, aflibercept) as monotherapy for the treatment of CNV associated with AMD. The use of anti-VEGF therapies for CNV secondary to other relatively rare disorders of choroidal circulation (angioid streaks, CSC, choroidal rupture or trauma, idiopathic CNV, multifocal choroiditis, pathologic myopia, presumed ocular histoplasmosis syndrome, and uveitis) is supported by a few small randomized trials, numerous case series, and clinical input. Therefore, anti-VEGF therapies (ranibizumab, bevacizumab, pegaptanib aflibercept) may be considered medically necessary for CNV associated with these conditions. Anti-VEGF therapies are considered investigational for the treatment of chorioretinal scars.

It is estimated that 40.9 million people over the age of 18 in the United States (one in six adults) wear contact lenses, 93 percent wear soft lenses and the rest have gas-permeable lenses. Contact lenses can be classified by their composition material, time of use, total time of use, permeability, water content, and type of correction. With many types of new lenses available, there are alternatives to help most patients achieve the use of comfortable lenses with clear vision. New types of contact lenses are being introduced continuously with the intention of reducing the risks of infection, inflammation and trauma of the conjunctiva and maximize vision correction and comfort of use Soft lenses are made of different plastic polymers that absorb water (hydrophilic). These materials differ in terms of oxygen permeability (expressed in Dk units, where D is diffusion and k for solubility), water content (which varies between 20 and 70 percent water by weight), quality of the surface (wettability), ultraviolet absorption, and structural consistency (rigidity or modulus). The Food and Drug Administration of the United States (FDA) has developed a classification system for soft lenses. The maintenance of a smooth and transparent refraction anterior surface is fundamental for good vision. A complex interaction between the cornea and the conjunctival epithelium, the tear film, and the overlapping eyelids offers protection against infection and scarring. Noninfectious complications are minimized with a contact lens with an adjustment that is both based on the pre-corneal tear film and moves just enough to allow good fluid and gas exchange, thereby functioning as a de facto extension of the ocular surface. <a id="

An intravitreal implant is a drug delivery system, injected or surgically implanted in the vitreous of the eye, for sustained release of a pharmacologic agent to the posterior and intermediate segments of the eye. Four intravitreal corticosteroid implants, ie, fluocinolone acetonide 0.59 mg (Retisert), fluocinolone acetonide 0.19 mg (Iluvien), fluocinolone acetonide 0.18 mg (Yutiq), and dexamethasone 0.7 mg (Ozurdex) are reviewed herein. Fluocinolone acetonide implants are nonerodible and deliver drug up to 30 to 36 months while dexamethasone implants are bioerodible and last up to 6 months. A punctum implant is a drug delivery device that is inserted through the lower lacrimal punctum into the canaliculus, for sustained release of a pharmacologic agent to the ocular surface. Dexamethasone ophthalmic insert 0.4 mg (Dextenza) is the first corticosteroid intracanalicular insert and is reviewed herein.

Intraocular radiation, including brachytherapy, proton beam therapy, and stereotactic radiotherapy, are being evaluated to treat choroidal neovascularization associated with age-related macular degeneration.

A retinal prosthesis replaces lost photoreceptor function by transmitting external images to an array of electrodes or via light sensors placed in the epiretinal or subretinal space. The artificial retina could restore sight to patients with blindness secondary to retinal diseases, such as retinitis pigmentosa, hereditary retinal degeneration, and some forms of age-related macular degeneration. Several models of retinal prostheses are in development in the United States, Europe, and Asia. Only the Argus II system has been cleared for use by the U.S. Food and Drug Administration (FDA).

Computer-assisted corneal topography (also called photokeratoscopy or videokeratography) provides a quantitative measure of corneal curvature. Measurement of corneal topography is being evaluated to aid the diagnosis of and follow-up for corneal disorders such as keratoconus, difficult contact lens fits, and pre- and postoperative assessment of the cornea, most commonly after refractive surgery.

Endothelial keratoplasty also referred to as posterior lamellar keratoplasty, is a form of corneal transplantation in which the diseased inner layer of the cornea, the endothelium, is replaced with healthy donor tissue. Specific techniques include Descemet stripping endothelial keratoplasty, Descemet stripping automated endothelial keratoplasty, Descemet membrane endothelial keratoplasty, and Descemet membrane automated endothelial keratoplasty. Endothelial keratoplasty, and particularly the specific techniques mentioned, are becoming standard procedures. Femtosecond laser-assisted endothelial keratoplasty and femtosecond and excimer laser-assisted endothelial keratoplasty have also been reported as alternatives to prepare the donor endothelium.