3

Overview of Selected Techniques for Diagnosing and Evaluating Patients

Over the past 30 years patient assessment and treatment have steadily transformed in the wake of scientific discoveries and technological innovations in fields such as computing, radiology, nuclear medicine, and genomics as well as in the social, behavioral, and health sciences. In the context of this study, the committee presents an overview of major techniques and trends currently in practice to assess patient health and functioning across different medical specialties. The discussion, organized by laboratory-based diagnostics, medical imaging, and functional assessments, provides background for chapters 4 through 8, which describe specific advances in the assessments of cardiovascular, neurologic, respiratory, hematologic, and digestive conditions, respectively.

LABORATORY-BASED DIAGNOSTIC MEDICINE

Clinical and Anatomic Pathology

Pathology is a medical discipline concerned with the cause, development, structural/functional changes, and natural history associated with diseases (Funkhouser, 2009). Clinical pathology, also referred to laboratory medicine, and anatomic pathology are two subspecialties integral to patient diagnosis and care (Lockhart, 2019). Fundamentally diagnostic pathology involves the examination of material obtained from the human body to determine whether the morphologic features (the form and structure of cells, tissues, or organs) match the set of diagnostic criteria for each disease (Chew and Tan, 2022; Funkhouser, 2009). In patient evaluations, clinical pathology studies

are common and are used several ways: in the examination of specific analytes in body fluids (e.g., cholesterol in serum, protein in urine, or glucose in cerebrospinal fluid); the specific identification of microorganisms (e.g., disease-causing bacteria in blood, respiratory viruses in respiratory secretions, or parasites in stool); the analysis of bone marrow specimens (e.g., the identification of a specific of type of leukemia); and the management of transfusion therapy (e.g., cross-matching blood products, or plasmapheresis) (NASEM, 2015). Additionally, there is a range of anatomic pathology studies that provide diagnostic information including surgical biopsy and the histologic (microscopic) evaluation of specimens, forensics (autopsies), and cytopathology. Cytopathology tests, which involve the examination of single cells or small clusters extracted from tissues, use the least minimal acquisition of tissue to make a diagnosis and can provide tissue used for molecular studies.

Molecular and Genetic Diagnostics

The role of pathology in the diagnostic process has expanded from morphologic observations into comprehensive analyses using combined histological, immunohistochemical, and molecular evaluations. New discoveries in molecular and cellular biology have provided insights into the mechanisms of disease at the level of biological molecules that are essential to life, which include carbohydrates, proteins, lipids, and nucleic acids. Molecular diagnostics (also called molecular pathology) combines laboratory testing, molecular biology, and advanced technologies and informatics “to investigate the human, viral, and microbial genomes, their genes, and the products they encode.” (CDC, 2023a). Molecular diagnostic testing enables the analysis of patient’s biomarkers in the genome, transcriptome, or proteome. The use of these tests is increasing in many areas of laboratory medicine including oncology, infectious diseases, clinical chemistry, and clinical genetics. For example, there are molecular diagnostic tests to detect common genetic mutations in tumors that inform diagnosis and treatment, identify the genetic material of organisms causing certain infectious diseases, and evaluate human DNA for inherited variants contributing to disease (AvaMedDx, 2013; NCI, 2023).

The past two decades have seen a revolution in gene sequencing for hereditary disorders. DNA sequencing--the process for determining the order of DNA nucleotides in an individual’s genetic code (MedlinePlus, 2023a)—was developed in 1977 and commercialized in 1986 (Sanger, 1988). It was not until the development of next-generation sequencing (NGS), around the middle of the 2000s, that the cost of DNA sequencing dropped substantially enough that the process could feasibly be used in diagnostics.

These genetic tests identify sequence variants that are found in the germ cells (eggs or sperm) of the patient and therefore are inherited within

a family. Variants that can be passed along to the next generation are called germline variants, and are found in all cells of the body including the germ cells. In contrast, some genetic variants are acquired mutations that develop due to errors of DNA replication. These are called somatic variants and are commonly found in cancer cells. Both germline and somatic variants are important to diagnose as they have implications for the treatment and progression of a disease over time and may also affect the prognosis for functional impairments for the patient.

The type of genetic testing a physician may order depends on the patient’s suspected health condition, the history of the patient and family members, other test findings, and other factors (CDC, 2023b). Single gene tests may be undertaken when the patient’s signs and symptoms are suggestive of a genetic condition caused by variants in a single gene (such as retinoblastoma, sickle cell disease, or Duchene muscular dystrophy) (GenomicsEd, 2023; CDC, 2023b). In comparison, gene panel tests look for variants in more than one gene and may be used to diagnose a person who has symptoms that may fit a wide array of conditions, or when the suspected condition can be caused by variants in many genes, such as epilepsy. If single gene or panel testing has not provided a diagnosis, or when the suspected condition or genetic cause is unclear large-scale, whole exome sequencing (WES) or whole genome sequencing (WGS) may be indicated. WES analyzes the coding regions of all the genes in the DNA (whole exome) and WGS analyzes all of a person’s DNA, not just the genes. These techniques identify genetic variations using NGS technology that allows the rapid amplification of large amounts of DNA in a short period of time. Several clinical applications exist for applying NGS to identify genetic mutations underlying disorders (Salunkhe et al., 2022). In oncology for example, targeted gene panels have been developed for detecting hereditary cancer, monitoring somatic changes in progressive cancer, and highlighting genetic aberrations that occur across multiple cancers (McCabe et al., 2019).

Despite the power of these advances to identify genetic changes, this is an evolving area of science and the significance of much of this information remains under study (MedlinePlus, 2023b). Since not all genetic changes affect health, it can be difficult to know which genetic variants are causing a patient’s clinical symptoms. Determining which genetic variants are pathogenic or likely pathogenic is the ongoing work of the Clinical Genome Resource (ClinGen), a program funded by the National Human Genome Research Institute. ClinGen experts curate and interpret gene variants as they are discovered and provide this information to ClinVar (National Library of Medicine, 2023), a publicly available database about human genomic variation and its relationship to human health, which is funded by the intramural research program of the National Institutes of

Health (NIH). As such, ClinVar is continuously updated with new information about the pathogenicity of genetic variants to aid clinicians in interpreting the impact of specific variants on the health of their patients.

Advances in the field of molecular diagnostics can be expected to continue to improve patient outcomes and quality of life by increasing diagnostic accuracy, enabling personalized medicine and disease management, and helping to reduce unnecessary treatments (NASEM, 2015). At the same time, the benefits of these tests may not be reaching people who may benefit. The CDC reports that valid and useful tests, such as those for hereditary breast and ovarian cancer or for Lynch syndrome, a form of hereditary colorectal cancer, are not widely used as a consequence of the limited research on “how to get useful genetic tests implemented into practice across U.S. communities.” (CDC, 2023c). The translation of molecular diagnostic technologies into clinical practice has been a complex and challenging endeavor (NASEM 2015). Although genetic tests have been developed for thousands of diseases, the scientific evidence underpinning the genetic tests for many of the diseases is lacking, and therefore tests may not provide valid or useful results (CDC, 2023c). One major challenge is the often time-consuming, expensive, and uncertain development pathway for the rigorous evaluation of a test before their implementation in clinical practice (NASEM, 2015). In addition, the standards of evidence for evaluating the scientific validity of these types of tests are insufficient and inconsistent, as are the study design and analytical methods for these analyses (IOM, 2007, 2010, 2012). There is considerable interest in ensuring the appropriate development and use of molecular diagnostic testing (CDC, 2023c; IOM, 2012); however, molecular diagnostic testing presents many regulatory, clinical practice, and reimbursement challenges (NASEM 2015).

MEDICAL IMAGING

Radiology is a branch of medicine that uses imaging technology to diagnose, treat, and monitor disease. The field of radiology also includes interventional radiology, which offers image-guided biopsy and diagnostic procedures as well as image-guided, minimally invasive treatments. Each modality is unique in terms of the images it gathers, equipment it uses, and conditions it helps clinicians diagnose. Specifically, the diagnostic imaging techniques described below include X-ray, computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI) as well as the nuclear medicine imaging technologies, positron emission tomography (PET) and single photon emission computed tomography (SPECT).

There are various technologies that underlie the different types of medical imaging techniques (COCIR, 2022). Some medical imaging techniques use ionizing radiation—a type of energy that atoms release in the form of

electromagnetic waves (gamma or X-rays)—to produce detailed images of the body (WHO, 2016). Specifically, ionizing radiation can create anatomical images (using X-ray or CT) as well as images of physiologic processes, known as functional images (using PET or SPECT). Ultrasound and MRI are techniques that do not use ionizing radiation. Diagnostic ultrasound transmits high-frequency sound waves into the body to produce images of organs and internal structures by converting the returning sound, echoes, into an image. MRI relies on magnetic fields and radio waves to produce detailed images of soft tissues in the body and is often used to evaluate blood vessels, breasts, bones and joints, soft tissues, and organs.

Molecular imaging is a growing discipline that integrates cell biology, molecular biology, and advanced imaging techniques to visualize and measure physiological or pathological processes at the cellular and molecular level in the body. Molecular diagnostic imaging can help detect the presence and extent of disease in its early stages, even before abnormalities can be detected with other diagnostic tests. The nuclear medicine techniques PET and SPECT are molecular imaging technologies that generate information about how tissues and organs are physiologically functioning. PET or SPECT scans can be combined with CT or MRI images of anatomical structures to provide clinicians with increased imaging detail. PET and SPECT are often used as diagnostic and follow-up modalities for neurological diseases such as Alzheimer’s disease and multiple sclerosis, cancer, heart disease, and gastrointestinal disorders, for example.

Over the past 20 years, improved scanner technology (e.g., X-ray photon detectors) and computing speed have contributed to the development and use of three-dimensional (3D) imaging (Horowitz, 2018). Compared to 2D imaging, 3D shows new angles, increased resolution of the images, and more precise detail of the anatomy. Multimodal imaging techniques produce additional clinical information pertaining to anatomic structures and functional processes by combining more than one imaging technique. For example, in 3D CT angiography (CT scan with bolus contrast injection), clinicians can visualize arterial and venous vessels to determine if a patient has vascular anomalies. Multimodal imaging using SPECT–CT, PET–CT, and PET–MRI for the purposes of diagnosis and treatment planning is increasing (Martí-Bonmatí et al., 2010). Overall, continued advances in computing technology and in artificial intelligence (AI) are expected to shape the future of imaging techniques (Horowitz, 2018).

In general, the interpretation of medical images is typically performed by radiologists or, for selected tests involving radioactive nuclides, nuclear medicine physicians. Technologists support the process by carrying out the imaging protocols. Most radiologists today have subspecialty training (e.g., in pediatric radiology or neuroradiology) (Blublth et al., 2014). The American Society of Radiologic Technologists (ASRT) developed the ASRT

Practice Standards for Medical Imaging and Radiation Therapy, which provides descriptions and practice parameters of the role and responsibilities of individuals within the profession (ASRT, 2022).

X-ray

Images of internal body structures, including bones, blood vessels, and soft tissues, can be produced by passing X-rays through the body. This radiation exits the body and interacts with an image receptor, such as film or a digital system. The exiting X-ray beam structurally represents the anatomic area of interest as a result of variations in the composition of anatomic structures that affect the absorption and transmission of the X-ray beam.

X-ray radiation can generate three kinds of medical images: conventional X-ray images, angiography, and fluoroscopy (COCIR, 2022).

• Conventional X-ray imaging produces a static image of a specific area of the body which can be used to detect the presence of anatomical abnormalities.
• Angiography uses X-rays in combination with a contrast agent (a substance that enhances specific structures in images) to visualize blood vessels.
• Fluoroscopy uses X-rays to visualize—and produce moving images of—internal structures in real-time, such as a heart beating or a throat in the process of swallowing.

Computed Tomography Scan

A computed tomography scan (CT scan) is an imaging technique that uses ionizing radiation (X-rays) to produce three-dimensional images of bones, muscles, fat, and organs. In a CT scan, X-rays are taken from different angles, with the resulting individual images processed by a computer to create tomographic images (i.e., cross-sectional images, or “slices”) which are digitally “stacked” together to form a 3D image of basic body structures which can be used to detect and monitor abnormalities within the body. Contrast agents may be used that are highly visible in an X-ray or CT scan and are safe to use in patients. For example, to examine the circulatory system, an intravenous contrast agent based on iodine is injected into the bloodstream to illuminate blood vessels and possible obstructions. Barium- or iodine-based contrast agents are used for imaging the digestive system, including the esophagus, stomach, and gastrointestinal tract (NIH, 2022a).

CT technology has greatly improved over the last 20 years, with it now being possible to create its reconstructed images at high resolution (Hussain et al., 2022). High-resolution CT (hrCT) is carried out with a modern CT

scanner but with higher-than-typical doses of radiation. Dual-energy CT is an increasingly available technique that lowers radiation exposure (Henzler et al., 2012). While the risks of CT are small, the risk of cancer from repeated CT scanning is increasing in the population, particularly in young children (Hussain et al., 2022). CT imaging protocols have been developed to minimize radiation exposure for patients who need serial CT scans for monitoring the progress of a disease.

Diagnostic Ultrasound

Diagnostic ultrasound uses high-frequency sound waves and a computer to detect changes in the appearance of blood vessels, tissues, and organs, and to detect abnormal masses. An ultrasound probe called a transducer is most often placed on the skin, but probes may be placed inside the body, for example, via the gastrointestinal tract, vagina, or blood vessels. The transducer sends sound waves into the body that bounce off organs and return to the ultrasound machine, producing an image for assessment. Diagnostic ultrasound can be used to diagnose many different conditions, such as those affecting the heart, kidneys, thyroid, gallbladder, and female reproductive system. Various types of ultrasounds are used for specific purposes, such as echocardiography, which produces images of the structure and function of a heart in real-time. There is also Doppler and color Doppler ultrasound that visualize and measure blood flow in vessels in the heart or within other areas of the body. To assess musculoskeletal function, dynamic ultrasound is used to assess muscle and tendon motion in vivo and has been shown to help in diagnosing a variety of musculoskeletal disorders such as slipping rib syndrome, ulnar nerve subluxation, and fasciculation (Chuang et al., 2016; Duarte et al., 2020; Van Tassel et al., 2019). Dynamic ultrasound is being used to develop quantifiable measures of musculo-tendon mechanical properties during movement (Sikdar et al., 2014).

Diagnostic ultrasound overall has benefited from faster and more powerful systems have allowed for signal enhancement and new ways of interpreting data, such as power Doppler and 3D imaging, which improve the quality of the image (BMUS, 2022; NIH, 2022b). Diagnostic ultrasound imagers are getting smaller and less expensive; currently palm-size ultrasound scanners are widening their application, for example, in remote locations that cannot support full-size scanners (NIH, 2022b).

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) uses computer-generated radio waves and a powerful magnetic field to produce three-dimensional detailed anatomic images. During the MRI scanning process, the machine’s magnet

produces a strong magnetic field. Hydrogen ions align within the patient due to the magnetic field. Bombardment by radiofrequency waves causes the alignment of lined-up hydrogen ions to move out and then return to the equilibrium state, resulting in a radiofrequency signal or “echo.” A series of smaller magnetic pulses during the procedure encodes the location of the produced echoes, and an attached computer system converts the echoes/signal into images.

The brain, spinal cord, and nerves as well as muscles, ligaments, and tendons can be seen more clearly with MRI than with regular X-rays and CT. In the brain, MRI is often used to diagnose aneurysms and tumors, among other pathologies. Unlike X-ray imaging and CT scans, MRI does not use damaging ionizing radiation; however, MRI is more expensive than these other methods (NIH, 2022c).

Use of MRI can be limited by a patient’s body habitus or claustrophobia, as these can make the MRI experience quite stressful for some individuals, although the stress can often be minimized with premedication or the use of open MRI scanners. One of the more serious contraindications for MRI is the presence of implanted devices, shrapnel, or other metal in the body. Magnetic fields produced by MRI scanners can cause dangerous interactions in patients with metallic foreign bodies, leading to such results as a projectile effect, twisting, burning, artifacts, and the malfunctioning of an implanted device (e.g., a pacemaker). Patients need to be thoroughly screened individually for foreign bodies before undergoing an MRI scan (Ghadimi and Sapra, 2022).

Nuclear Medicine

Nuclear medicine is a medical specialty that uses radioactive tracers, also called radiopharmaceuticals, to diagnose and treat disease. Radioactive tracers are made up of carrier molecules—specific to the purpose of the scan—that are bonded to a radioactive atom. FDA-approved radiopharmaceuticals must meet standards for safety and clinical use. A nuclear medicine physician will select the tracer specific to patient’s particular problem. After the radioactive tracer is administered to the patient, the path of the radioactive tracer is tracked using specialized imaging instruments, most commonly either PET or SPECT. A main difference between SPECT and PET scans is the type of radiotracers used (NIH, 2022d).

PET and SPECT instruments provide 3D computer-generated images of the distribution of radioactive tracer molecules in the patient’s body. In the last 2 decades, the quality of images acquired with PET and SPECT has vastly improved, “making it possible to detect a defect less than a few millimeters in diameter” (Niimi et al., 2017, p. 331). SPECT scans are primarily used to diagnose and track the progression of heart disease, such as

blocked coronary arteries, and gastrointestinal disorders. For example, to determine the exact source of intestinal bleeding, a radioactive atom may be added to a sample of the patient’s red blood cells, with the resulting composite injected back into the patient; a SPECT scan follows the path of the radio-labeled blood to identify any accumulation of radioactivity in the intestines, which will indicate an area of bleeding. More recently, SPECT agents have become available for aiding in the diagnosis of Parkinson’s disease (NIH, 2022d) (see Chapter 5), and there is a new application of a bone avid SPECT tracer in the noninvasive diagnosis of cardiac transthyretin (TTR) amyloidosis (see Chapter 4).

Multimodality imaging techniques that use SPECT and PET are relevant to several clinical applications, such as oncology, cardiology, and neuropsychiatry (Martí-Bonmatí et al., 2010). PET scans using F-18fluorodeoxyglycose, a radiotracer of glucose metabolism, are commonly applied to detect cancer and monitor its progression and the response to treatment. Concomitant PET and CT imaging of the same body regions using a PET/CT scanner has become the primary imaging tool for the staging of most cancers. Recently, the U.S. Food and Drug Administration approved a PET probe that can aid in the accurate diagnosis of Alzheimer’s disease (NIH, 2022d).

In cardiac applications, the benefits of PET over SPECT include (1) higher resolution and diagnostic accuracy, (2) lower radiation exposure due to the much shorter half life of cardiac blood flow tracers like rubidium-82 (75 seconds) and nitrogen-13-ammonia (10 minutes) compared with technetium-99m-labeled agents (6.03 hours), and (3) the ability to quantify myocardial blood flow in absolute terms (in ml/min/g of myocardium) versus relative quantitative or qualitative assessment of myocardial perfusion defects. Modern cardiovascular imaging technologies, such as cardiac PET, stress-first SPECT with use of newer cadmium-zinc-telluride cameras, and prospective electrocardiogram-gated coronary computed tomography angiography (CCTA), described in Chapter 5, use vastly lower doses of radiation than the nuclear and CT technologies of the past.

PET scans and SPECT scans are performed by skilled technicians at highly sophisticated medical facilities in a hospital or at an outpatient testing facility. Overall, SPECT scanners are cheaper and more readily available than the higher-resolution PET equipment.

Appropriate Use of Medical Imaging

To guide and inform clinician and patient decisions about the appropriate use of medical imaging, the American College of Radiology (ACR) Appropriateness Criteria® (ACR, 2022) are clinical practice guidelines for diagnostic imaging selection, radiotherapy protocols, and image-guided

interventional procedures. The ACR Appropriateness Criteria present current evidence for selecting appropriate diagnostic imaging and interventional procedures for numerous clinical conditions, including conditions related to this study (i.e., cardiac, vascular, gastrointestinal, neurologic, and pediatric conditions).

To enforce a provision in Public Law 113–93, Protecting Access to Medicare Act of 2014, Section 218(b), the Centers for Medicare & Medicaid Services (CMS) has mandated the use of appropriate use criteria (AUC) for advanced diagnostic imaging services ordered for Medicare beneficiaries. Providers are required to consult the relevant AUC at the time of a test order, using a qualified clinical support decision mechanism (i.e., an electronic portal), in order to receive reimbursement from CMS as deemed appropriate. Examples of advanced imaging procedures under the program include CT, MRI, and nuclear medicine studies, including SPECT and PET. CMS is continuing the testing period for the imaging AUC program until further notice and is not forecasting when the payment penalty phase will begin (CMS, 2022).

DIGITAL DIAGNOSTIC TECHNOLOGIES

Artificial intelligence (AI) and machine learning (ML) are expected to increasingly influence digital health care and patient diagnosis and treatment. Used in the detection of disease, AI and ML in medicine are enabling rapid, computer-generated interpretation of tests and the detection of signals and patterns not identified by humans, with precision. One example is AI-enhanced electrocardiogram (ECG) used in the detection of cardiovascular disease in at-risk populations (Siontis et al., 2021). In stroke, AI software has been developed for use with CT or MR imaging to identify acute ischemic brain tissue pathology, arterial obstruction, and brain hemorrhage, for example (Soun et al., 2021; Wardlaw et al., 2022); additional validation studies are expected to increase its use in clinical practice (Soun et al., 2021). AI and ML are also contributing groundbreaking knowledge about the cellular architecture of human diseases, including cancer (Iqbal et al., 2021). Applications using AI combined with telehealth may prove to be diagnostically useful in the future.

In addition, remote patient monitoring devices that measure or detect common physiological parameters and wirelessly transmit patient information to healthcare providers are becoming more available for the assessment and monitoring of patient health and functioning (FDA, 2023). The use of remote monitoring devices in patient diagnosis and care management can augment episodic in-person evaluations. Remote tools can serve as potential confirmation or refutation of in-person assessments of functioning, for example. There are different types of remote devices for assessing

and monitoring cardiovascular functions, sleep, brain activity, and physical function and activity level, such as walking, as studies show the amount and cadence of person’s steps are related to cardiovascular and dementing illnesses (del Pozo et al., 2022a, 2022b). Emerging remote monitoring devices include, for example, devices that facilitate the diagnosis of pediatric autism spectrum disorder (Schuman, 2021) and the monitoring of tremors in Parkinson’s disease (Chandrabhatla et al., 2022; Powers et al., 2021).

FUNCTIONAL ASSESSMENTS

In Chapter 2, the committee discusses how functional assessments contribute to a more accurate understanding of patient functioning and highlights the importance of using information from functional assessments to assess disability. This section refers to measures that capture functioning at the level of the organ or organ system (i.e., body function) as well as measures that capture functioning at the level of the whole person (i.e., the activity and participation components of the International Classification of Functioning, Disability and Health model in Chapter 1). Patient-reported and performance-based measures of physical function (such as cardiopulmonary exercise testing and the 6-minute walk test) provide complementary information and together can be used assess an individual’s overall functional status. Reviewing the full range of new and improved functional assessments goes beyond the committee’s task, given the very large number of tests available. Over the last 30 years, extensive efforts have been made to develop new instruments or improve upon the accuracy, precision, methods, and scope of existing instruments. As an example, one recent study validated the inclusion of 20 new activities-of-daily-living tasks to the existing Assessment of Motor and Process Skills (Bray et al., 2001). In addition, there is growing use of computer adaptive testing, which uses algorithms to adjust to the participant’s ability level. It is a set of questions or items (called an item bank) to which the respondent indicates their level of ability to perform the activities. For instance, a computer adaptive test of mobility uses a survey approach that asks the respondent how much difficulty they have walking on an incline. If they respond that they have a lot of difficulty or cannot do it, the next question would ask about an easier mobility task. If they indicated that they have no difficulty, the next question would ask about a harder mobility task (Haley et al., 2006). The advantages over standard non-automated instruments include, for instance, allowing a more accurate assessment of a person’s abilities in real-time with less time needed to perform the test. There are many resources providing information about specific functional assessment measures. A current resource on the topic, Functional Assessment for Adults with Disabilities (NASEM, 2019), is a comprehensive review of the literature pertaining to

the functional assessment of physical and mental health abilities relevant to work requirements. The report includes a compilation of selected instruments for the general assessment of physical function and for measuring musculoskeletal function, pain, visual function, hearing function, and speech and language function. Details are provided on over 60 selected functional assessment tools for physical abilities, including the qualifications needed to administer the test, how to administer it, time to administer it, its psychometric properties, proprietary considerations, and the populations to which the tools apply. Another resource is information from the American Academy of Physical Medicine and Rehabilitation (AAPM&R). AAPM&R’s website (Borras-Fernandez et al., 2016) identifies many different functional assessment scales that evaluate, for example, the performance of basic functional skills required to care for oneself independently, the effects of executive function deficits on everyday functioning through real-world tasks, the severity of pain, and functional tolerance (based on a medical condition) that is safe for a worker to perform. Detailed tables provide information about the test’s purpose, length, training required to administer, number of items, equipment needed, cost, and target population. Lastly, the National Institute of Neurological Disorders and Stroke’s Common Data Element (CDE) provides a searchable database of functional assessment instruments and other measures applicable to the evaluation of a wide range of neurological diseases and conditions. CDE measures were vetted by panels of experts and found to be psychometrically sound with substantial evidence supporting their use (NINDS, 2023).

Patient-Reported Measures

A wide range of functional outcomes can be measured using patient-reported instruments, including return to work, physical function, cognitive function, emotional function, support network, and social supports. Findings based on validated patient-reported measures often correlate with results from physical performance measures or clinical examinations. In addition, research shows that patient-reported outcomes are interrelated: mental (emotional and cognitive) function predicts and is predicted by physical function outcomes (Csajbók et al., 2022; Sewell et al., 2021). Below are a few examples of validated tools for measuring multiple functional outcomes and symptoms using patient-reported data.

• PROMIS^® is a publicly available system of over 300 rigorously tested, reliable, and precise measures of patient-reported health status for physical, mental, and social well-being. PROMIS can be used with the general population and with adults and pediatric populations living with chronic conditions. PROMIS measures

health symptoms and health-related quality of life domains such as pain, fatigue, depression, physical function, and social function. PROMIS measures are available in many different languages (HealthMeasures, 2022a).

• NIH Toolbox® includes many measures to assess cognition, emotion, motor function, and sensation. The NIH Toolbox contains performance-based tests of function and self-report and proxy measures that are used in the general population and in individuals with chronic conditions, across the lifespan. Many of the measures can assess function from early childhood, while others target specific age bands (HealthMeasures, 2022b).
• Neuro-QoL^TM (Quality of Life in Neurological Disorders) is a measurement system that evaluates and monitors the physical, mental, and social effects experienced by adults and children living with neurological conditions. Among the conditions addressed are stroke, multiple sclerosis, Parkinson’s disease, epilepsy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and Huntington’s disease (HealthMeasures, 2022c).
• The FACIT (Functional Assessment of Chronic Illness Therapy) Measurement System, developed in 1997, is a compilation of over 100 distinct self-report questionnaires that assess a wide variety of symptoms, functional abilities, general perceptions of health and well-being, and other aspects of health-related quality of life in adults and children. FACIT includes questions addressing four primary quality of life domains: physical well-being, social/family well-being, emotional well-being, and functional well-being. FACIT scales are constructed to capture clinically relevant problems associated with a given condition or symptom, and they allow for comparison across diseases (FACIT, 2022).

Whether self-, or interviewer-administered, the accuracy of survey information is based mainly on respondent characteristics, including abilities, knowledge, motivations, and competing burdens (NASEM, 2019). The accuracy of self-reported information can be affected, intentionally or unintentionally, by the respondent. For example, some individuals who want their condition or the magnitude of their perceived distress to be taken seriously may overestimate their difficulty in performing various tasks. Conversely, other individuals may overestimate their abilities out of a desire to please the interviewer or to maintain independence or not appear weak. In addition, certain individuals, for example, some with traumatic brain injury or stroke, may have poor self-awareness or an inability to assess their limitations accurately because of a neurological deficit (e.g., anosognosia). The use of instruments or test batteries that include validity measures can

help testers determine the validity of the results obtained (IOM, 2015). Another consideration is gender, racial, ethnic, and cultural variation in individuals’ perceptions of illness and symptoms and whether relevant self-report measures have been assessed for equivalency of scores in different populations (NASEM, 2019).

Performance-Based Exercise Tests

It has long been recognized that evaluating individuals while they are actively exercising can unmask medical conditions that are undetectable at rest or identify limits to function that are poorly predictable from resting measurements. The major advantages of exercise tests are that they quantify impairment in function of the whole individual, rather than of an isolated aspect of an individual organ system, and that they do so under the physiologic stress of physical activity and reflect aggregate effects secondary or coexisting conditions on function as well as the primary diagnosis. Much early medical exercise testing focused on the identification of exercise-induced myocardial ischemia, which remains the most common medical use of exercise testing. A standardized, multi-stage treadmill protocol with ECG monitoring for this purpose was first published by Bruce and colleagues in 1963 and remains in wide use. The Bruce protocol and many others use graded (increasing) levels of difficulty, generally terminating in maximal exercise performance, so they have evaluative as well as diagnostic functions. Graded exercise testing with ECG monitoring is referred to here as routine cardiac stress testing and described briefly for comparison with cardiopulmonary exercise testing, which uses similar profiles and modes of exercise. In addition to graded tests performed in laboratories, there are many low-technology performance tests used for field testing, epidemiological studies, and clinical research. These may measure tasks performed in a defined time or measure the time required to perform a defined task. Some, such as the 6-minute walk test, have been incorporated into clinical practice for evaluative testing.

Routine Cardiac Stress Testing

Cardiac stress testing is usually performed on a treadmill or cycle ergometer with monitoring of the continuous ECG and blood pressure. It is most commonly used to identify exercise-induced myocardial ischemia and arrhythmia on ECG. Myocardial ischemia can develop due to a supply–demand imbalance in myocardial oxygen. Because myocardial oxygen demand is typically proportional to heart rate and systemic blood pressure, the adequacy of a stress test for assessment of inducible ischemia may be judged by the heart rate response or the rate–pressure product, calculated

as systolic blood pressure times heart rate. In selected patients, evidence of ischemia may also be evaluated using nuclear medicine or echocardiographic imaging in conjunction with exercise stress, particularly if the ECG is not adequate for interpretation.

Encouragement is given during graded testing for the patient to continue exercising to symptom-limitation by shortness of breath, fatigue, chest pain, or non-cardiac symptoms such as orthopedic conditions. Early termination by professional staff is indicated if there are adverse events such as a drop in blood pressure, limiting chest pain, or evidence of severe ischemia or high-grade arrhythmias. Such events generally are considered sufficient evidence of cardiac limitation even if the test was stopped early. The termination of uncomplicated tests on attainment of a pre-specified criteria such as a percent of the predicted maximal heart rate is not recommended, as this may underestimate maximal exercise capacity and limit diagnostic utility.

Professionals administering stress tests need to be experienced in recognizing the typical signs of disease and risks during the test as well as in assessing the individual’s degree of effort. An individual’s intentional restraint of effort can be suspected from a lack of typical heart rate and blood pressure changes or from the appearance of vigorous effort during exercise. More difficult is distinguishing individuals with true cardiac limitations from those who are peripherally deconditioned as a result of prolonged inactivity or of non-cardiovascular pathology.

Although the assessment of functional capacity from routine stress testing is sometimes expressed as the total exercise time on a standardized test protocol, it is recommended that it be expressed as well as by the total body oxygen consumption attained, estimated from the peak settings attained on the ergometer and given in terms of metabolic equivalents (METs). METs are multiples of the resting metabolic rate, which by convention is assumed to be 3.5 ml/min/kg of oxygen consumption (V^∙O₂)_. During exercise, total V^∙O₂ increases, almost entirely due to an increase in skeletal muscle metabolism. For reference, walking on level grade at 2.5–3.5 miles per hour is estimated to require 2.9–3.5 METs or a V^∙O₂ of 10.2–12.9 ml/min/kg. An inability to perform 5 METs (a V^∙O₂ of 17.5 ml/min/kg) without symptom limitation is generally sufficient to meet the current Social Security Administration listing for cardiac or pulmonary disability (SSA, 2018). An estimation of the V^∙O₂ from the external workload performed during exercise requires important assumptions, however. The first is that the metabolic work of performing an activity per kilogram of body weight will be the same for everyone, ignoring differences in ergonomic skill in performing the task. The second is that the temporal relationship between changing work rate and changing metabolic rate during the non-steady-state conditions of a graded exercise test protocol will be the same in tested individuals as it is in normal healthy persons. Both assumptions may be invalid in clinical populations. For example,

with respect to the first, someone with an inefficient gait due to an orthopedic condition may require more energy and higher V^∙O₂ than expected to walk at a given speed and grade. Conversely, the use of the handrails on a treadmill during testing can significantly reduce the V^∙O₂ relative to what it is assumed to be. With respect to the second assumption, an important aspect of many chronic cardiovascular, pulmonary, and muscle disorders is abnormally slow adjustment of V^∙O₂, or failure of adequate adjustment, to progressively higher work rates. As a result, the actual metabolic rate achieved during the test can be substantially less than assumed for the peak external work on the ergometer. For these reasons, the estimated METs for work rates attained during a routine exercise test may be inaccurate.

Professionals administering stress tests need to be experienced in recognizing typical signs of disease and risks during the test as well as in assessing an individual’s degree of effort. An individual’s intentional restraint of effort can be suspected from a lack of typical heart rate and blood pressure changes or from a lack of the appearance of vigorous effort during exercise. More difficult is distinguishing individuals with true cardiac limitations from those who are peripherally deconditioned as a result of prolonged inactivity or as a result of non-cardiovascular pathology.

Cardiopulmonary Exercise Testing

Cardiopulmonary exercise testing (CPET) is used to assess maximal aerobic capacity in healthy persons and in individuals with chronic diseases. In addition to evaluating exercise capacity, CPET has diagnostic applications as well, particularly for cardiovascular and pulmonary abnormalities. CPET involves exercise stress testing with simultaneous gas exchange analysis. Measurements are made of pulmonary ventilation (V^∙E) and gas exchange (the rates of oxygen uptake [V^∙O₂] and of carbon dioxide output [V^∙CO₂]) as well as of ECG and blood pressure. Like routine stress tests, test protocols are usually graded and symptom-limited, with the goal of identifying an individual’s maximal or peak V^∙O₂, which is the accepted standard for quantifying exercise capacity. CPET usually involves the use of either treadmill or cycle ergometer exercise. To enable measurement of gas exchange and VE, the individual being tested breathes through a mask or mouthpiece. Flow rate and gas tensions of respired breath are used to calculate gas exchange and related variables. In addition to the ECG and blood pressure, pulse oximetry is usually measured as an estimate of arterial oxygen saturation (SpO₂). According to a statement of the American Thoracic Society/American College of Chest Physicians on cardiopulmonary exercise testing, such testing “complements other clinical and diagnostic modalities and by directly quantitating work capacity improves the diagnostic accuracy of impairment/disability evaluation . . . [and] may be particularly

helpful when job-related or exertional complaints are disproportionate to the measured . . . impairments” (ATS and ACCP, 2003, p. 217).

CPET has several advantages over other techniques. Taking measures of resting organ system function alone by, for example, spirometry, ECG, or echocardiogram may not identify or quantify impairments that account for symptoms or limitations occurring during activity. In addition, routine stress tests without a simultaneous assessment of gas exchange and ventilation may not provide enough information to verify that a limitation was reached or to identify its cause. The ability to determine the anaerobic threshold (or ventilatory threshold is a unique advantage of CPET. It provides information on the individual’s anaerobic threshold, or the level of work he or she would likely be able to sustain for at least 50 minutes (if not limited by other conditions) (NASEM, 2019). CPET expands the range of assessments made during exercise to include a number of aspects of heart and lung function which are useful in diagnosis as well as in attribution of the cause of limitation. In contrast to CPET, diagnostic tests that are performed at rest may measure one aspect of an organ system function and may not accurately predict how a measured impairment will affect the ability to perform activity. Routine exercise stress tests may overestimate or underestimate overall impairment because of differences in metabolic and external work and the inability to identify inadequate effort. Also, routine exercise stress tests have limited diagnostic information. Self-paced performance tests are prone to underestimating functional capacity because they are not designed as maximal tests and lack measurements that assess the degree of cooperation and effort. CPET measures a wider range of variables and so is better able to identify factors limiting exercise other than ischemia or arrhythmia and to quantify variables that have prognostic value in specific clinical conditions.

Concerning the limitations of diagnostic CPET, many abnormalities identified from testing could be common to several different pathologic conditions. The test is often most useful for making broad distinctions, e.g., between pulmonary and cardiac etiologies, rather than establishing a highly specific diagnosis (Palange et al., 2007). Its diagnostic utility is dependent on interpretation of the test results in light of other clinical history and findings. In some circumstances, other established diagnostic procedures may be combined with CPET to increase diagnostic specificity. An example of this is invasive CPET, which uses a right heart catheter to measure hemodynamics during exercise.

CPET frequently is performed in pulmonary function laboratories or cardiac stress testing laboratories in community or academic hospitals and clinics. A review of published literature does not identify specific disparities in access to this type of testing related to racial, ethnic, socioeconomic factors. However, the specialized expertise in the use and interpretation of

CPET is not uniformly available in all health care settings; there is greater access to CPET at major medical centers, academic centers, and in practices that specialize in care of clinical populations for which CPET is most widely indicated, such as advanced heart failure, congenital heart disease, or the problem of unexplained dyspnea.

Six-Minute Walk Test

The 6-minute walk test (6MWT) is one of many performance tests requiring minimal technology used as an indicator of the functional status of individuals with a known underlying condition (Holland et al., 2014). Originally reported as a shorter version of the 12-minute walk test and advocated for evaluation of military personnel, the 6MWT was proposed as more suitable for testing patients (Butland et al., 1982). In 2002 the American Thoracic Society published standardized protocols to improve the test’s reliability, which have been widely adopted (ATS, 2002). These were updated with little change in 2014 (Holland et al., 2014).

The 6MWT involves encouraging a patient to cover as much distance as possible along a measured corridor during a 6-minute period. This method is self-paced and that is so highly dependent on an individual’s level of effort, which may be reduced during an evaluation for disability. The gait speed measured during a shorter 4- to 6-meter walk is gaining popularity as an index of frailty in populations with chronic disease (Peel et al., 2013), but it is also highly dependent on effort and has not been compared against work requirements. Standardized protocols for conducting the 6MWT have been developed to improve the reliability of the results (ATS, 2002; Holland et al., 2014). In some clinical populations, the 6-minute walk distance correlates with peak V^∙O₂, making it an index of maximal exercise capacity, but this is variable among conditions and individuals.

Over the last several decades the 6MWT has emerged as a useful tool for serial assessments of exercise performance in clinical trials of interventions for a range of conditions, including chronic lung disease, pulmonary hypertension, and heart failure. The relationships between 6MWT distance and other measures such as peak V^∙O₂ from CPET and the value of the 6MWT results as a predictor of outcomes in chronic disease are variably reported, perhaps reflecting differences in the specific conditions or disease severity in the study cohorts. (Agarwala and Saltzman, 2020; Lucas et al., 1999). In some conditions the 6MWT is used in conjunction with other information in a clinical assessment of disease severity.

Diagnostic tests of resting organ system function may not reflect the net effect of impairment on overall functional capacity. Functional performance tests, including the 6MWT, are more likely to capture the effects on physical performance of secondary and coexisting conditions, such as disease in

other organ systems, frailty, obesity, deconditioning, and sarcopenia. Other exercise tests, such as CPET, include a broader range of measures and are designed to determine maximal capacity but require specific equipment and technical expertise. The 6MWT, by contrast, provides information on functional status and relates to quality of life while requiring minimal equipment and technical expertise (Agarwala and Salzman, 2020).

Disparities in access to 6MWT due to racial, ethnic, socioeconomic or geographic lines have not been identified (Singh et al., 2014). The recommended use of a standardized script for instruction and encouragement during testing raises the potential of disparities related to language, as these materials are most widely available in the United States in English.

There are many performance tests or field tests used in the assessment of physical function, including other time-limited distance tests, timed tests of defined distance, incremental speed walk tests, step tests, and others (Singh et al., 2014). In the United States, the 6MWT has been used more widely than most other tests and has been applied in a wide variety of clinical populations. There are both normative data related to 6MWT distance in healthy individuals selected in various ways and also data on the prognostic significance of 6MW distance in a number of chronic disease populations. So while the 6MWT is not necessarily superior to other functional tests, the volume of comparative data makes it among the more useful. Acceptance of standard protocols for performance of the test makes results more generalizable than tests without such standardization. As noted previously, the physical and technical requirements for test performance are minimal.

The outcome of the 6MWT is distance walked in 6 minutes expressed in meters. Most 6MWTs are performed before and after an intervention or over the course of disease progression or treatment, and the question to be answered is whether there has been a clinically significant change in a person’s score. The American Thoracic Society recommends that changes in distance on repeat testing be expressed in terms of absolute value (e.g., the patient walked 50 meters further) (Agarwala and Salzman, 2020). Minimally clinically important differences of around 30 m have been estimated for changes in 6MWT distance from clinical cohorts (Puhan et al., 2011), idiopathic pulmonary fibrosis patients (du Bois et al., 2011), and pulmonary arterial hypertension (Mathai et al., 2012). A secondary outcome of 6MWT sometimes included in tests of individuals with lung disease is oxygen saturation from pulse oximetry.

For this test the patient is asked to walk as far as possible back and forth in a flat corridor for 6 minutes. Factors that can affect the distance walked include track layout (continuous versus straight) and length, oxygen in the air, verbal encouragement, and the learning effects (i.e., repeated trials) (Agarwala and Salzman, 2020). Using standardized methods is essential

for reliable results. This includes use of a minimally trafficked level grade corridor with a track 30 m in length; however, reference equations exist for 20-m and 10-m tracks in the event that a 30-m track is unavailable; repeat testing should always use an identical track. Longer or continuous tracks generally result in greater walk distances due to the time taken for turns. Treadmill walking differs from free-range walking and so does not yield comparable distances. Standard scripted instructions are available and should be adhered to closely. Changes in the wording, frequency, or content of instructions affect walk distances. There is a systematic learning effect between the first and subsequent 6MWT distances. To account for this, an initial familiarization test should be performed to establish the baseline distance (Agarwala and Salzman, 2020). The technician performing the test should be certified in cardiopulmonary resuscitation and trained in the use of the standard protocol and supervised for several tests before performing them alone. Physician attendance is usually not required (ATS, 2002).

There are a few impediments to the performance of 6MWTs, the most common being access to an appropriate 30-m indoor track. The 6MWT is an evaluative, rather than diagnostic, test. Because it is explicitly a walking test, it has a ceiling effect related to the effective upper limit of walking speed. It therefore is likely to be insensitive to the presence of, or changes in, mild disease. It is self-paced so that individuals’ perceptions of the instructions and motivation to perform the test optimally affect the outcome. Standardized testing procedures, including scripted instructions and feedback are important for minimizing variability and increasing confidence in test results.

REFERENCES