Identifying implementation strategies to increase the early detection of cardiac amyloidosis: a pre-implementation study

Abstract

Introduction:

Cardiac amyloidosis (CA) has been considered a rare disease. However, its prevalence is growing as healthcare practitioners have new, less invasive diagnostic tools that aid in the early detection of this disease. Bone scintigraphy with monoclonal protein testing is one such evidence-based, noninvasive screening option that can be offered in community healthcare facilities. This work aims to identify intervention strategies to improve the timely workup of transthyretin CA, including evidence-based practices such as bone scintigraphy and monoclonal protein testing.

Methods:

The team used rapid qualitative content analysis to develop a system map of care for cardiac amyloidosis, guided by both patient and healthcare expert perspectives. To explore the map's utility and accuracy, the team conducted follow-up in-depth interviews with clinicians. They explored clinicians' perspectives on strategies to facilitate the early diagnosis of CA and explored barriers and implementation strategies that can influence the diagnostic work-up for CA.

Results:

Clinicians provided recommendations for how to expand the map, particularly in terms of including additional healthcare professionals, screening strategies, and barriers to care for patients. After expanding the preliminary system map of care, the team identified 23 distinct strategies to improve the early detection of CA. Clinicians recommended additional strategies, such as patient and provider education, patient take-back, the use of artificial intelligence with electronic health record data, and the formation of healthcare teams specializing in cardiac amyloidosis, to enhance early detection and treatment of this condition.

Discussion:

This work can inform researchers and clinicians about selecting and implementing intervention and implementation strategies within health systems to enhance the early detection of cardiac amyloidosis.

1 Introduction

Advances in non-invasive diagnostics have led to rapid increases in diagnosing cardiac amyloidosis (CA), once considered a rare condition that, when undetected and untreated, leads to premature mortality, loss of physical function, and poor quality of life (1). These different CA conditions differ in the types of proteins that misfold, their prognosis, and the treatments they require (2). Further, ATTR-CA is more common than AL-CA (3), with an estimated US prevalence of 50,000–100,000 (4).

Patients with ATTR-CA often develop heart failure (HF), atrial fibrillation, and non-cardiac conditions such as neuropathy, spinal stenosis, and carpal tunnel syndrome (5). These symptoms are common and seemingly unrelated; therefore, clinicians may miss opportunities to diagnose CA. It is essential to describe both current and ideal clinical practices for the early diagnosis of ATTR-CA because awareness and communication of the constellation of early warning signs could save lives (6). However, despite ongoing advancements, including non-invasive diagnostic testing for CA (7), this systemic disease remains underdiagnosed and misdiagnosed, and is subject to diagnostic delays (8).

An evidence-based diagnostic work-up strategy, bone scintigraphy coupled with monoclonal protein testing, can identify patients with ATTR-CA or AL-CA. Bone scintigraphy, a nuclear medicine imaging technique (Tc-99 m PYP [pyrophosphate] or Tc-99m-HMDP [hydroxymethyl diphosphonate]), in combination with monoclonal protein testing, offers significant diagnostic opportunities, with a sensitivity of >99% and a specificity of 86% for detecting ATTR-CA (9). Patients with a characteristic scintigraphy scan and absence of monoclonal proteins do not require endomyocardial biopsy. Biopsy requires a heart tissue sample and is most often performed in advanced HF tertiary centers, whereas scintigraphy can be performed in all settings, including community healthcare facilities. As such, in 2022, the American College of Cardiology and the American Heart Association Heart Failure guidelines recommended that clinicians order bone scintigraphy and screen for light chains via monoclonal protein testing in patients with a clinical suspicion of CA (9). Despite this clear recommendation, suboptimal uptake of this workup strategy is likely, given healthcare providers' low clinical suspicion for ATTR-CA, which influences the tests, clinical work-up, and diagnoses patients receive (10).

Two research questions that guided this work include: (1) What are the barriers for patients to receive the work-up for the early diagnosis of CA (bone scintigraphy coupled with monoclonal protein testing)? and (2) What intervention strategies can lead to the evidence-based work-up for CA (bone scintigraphy coupled with monoclonal protein testing)? For this research, we utilized the first sets up the System Evaluation Theory (SET) to map the system of care and identify implementation strategies that lead to the timely workup for ATTR-CA (11). Another article describes the steps for utilizing SET and creating and updating the system map, including specific updates from the original draft to the final system map in greater detail (12). However, this exploratory study focuses on identifying implementation strategies and applying it to well-known implementation strategies for future implementation science research aimed at increasing the timely uptake of bone scintigraphy and monoclonal protein testing.

2 Materials and methods

We received Institutional Review Board approval from the Arizona State University Institutional Review Board (STUDY00017092). We first created a preliminary system map of care for the early detection of ATTR-CA that also serves as a standard operating procedure for the early diagnostic work-up for this condition. The map was informed by an expert panel of clinicians who treat CA patients and two CA patients. We conducted follow-up in-depth interviews with the clinicians to refine and update the map and to develop implementation strategies to increase uptake of the evidence-based approach to detecting CA using bone scintigraphy and monoclonal protein testing. Below, we describe these methods in more detail.

2.1 Expert panel participants

Using purposive sampling, the research team invited CA experts and patients attending a day-long CA symposium (a day-long CA symposium hosted on January 14, 2023) to participate in a 3-hour workshop panel on early detection of CA. CA experts in the panel represented multiple disciplines involved in the care of amyloidosis patients. The cardiologist who planned the CA symposium ensured the panel was diverse and contained the necessary expertise to provide input on the early detection of CA. An expert amyloid cardiologist identified two CA patients with different forms of the condition (e.g., one caused by ATTR and one caused by AL) to describe their experiences leading to the diagnosis of CA. See Table 1 for a description of the workshop attendees.

All participants completed written informed consent. The team conducted and recorded the panel discussion. A professional transcription company transcribed the panel discussion, and the research team conducted a matrix analysis to organize the results of this interdisciplinary audience of providers and patients (13). The team, comprised of clinicians, social science researchers, and a SET expert, met weekly to discuss the matrix analysis and to gain consensus on their coding. At this stage, the team did not seek information saturation, given that the goal was to map the various responses.

2.2 Follow-up interviews

Following the panel, the research team created a preliminary system map—a visual depiction of the steps leading up to bone scintigraphy and monoclonal protein testing—and recorded a video presentation of the map, which was emailed to all workshop clinician participants (See Table 1 for their expertise). This was also a method of member-checking, ensuring that the preliminary system map aligned with participants' shared perspectives. Patients were not interviewed at this stage of the research due to their lack of experience in healthcare delivery. The video presentation described the aim of refining the systems map and developing implementation strategies to increase the early detection of CA. Between April and June 2023, the research team invited participants to a web-based (Microsoft Teams) hour-long in-depth interview designed to refine the existing map and identify barriers and facilitators for implementation. (See Appendix 1 for the interview guide.) Two qualitative research experts (initials blinded for review) with doctorates in the health sciences took turns leading the interviews while the other took field notes. Additionally, team clinicians (initials) attended the interviews to ask follow-up questions or clarify clinical information. All follow-up interview participants completed written informed consent. The follow-up interviews lasted, on average, 62 min (range = 39.4–80.5 min). The team contacted one participant after her interview to clarify an implementation strategy that she proposed. Upon completing the in-depth interviews and reviewing the interview transcripts generated in Microsoft Teams, the team used a qualitative content analysis approach, hand-coded transcripts and documented additional barriers, clarifications to the system map, and new implementation strategies. Similar to the matrix analysis, the team did not seek information saturation given the small sample size of various healthcare professionals. They integrated the new content into the preliminary systems map.

All study members reviewed the transcripts for clarity, completeness, and consistency, documented barriers to early detection of CA, and ensured that the implementation strategies identified in the interviews were appropriately categorized and added to the map. Additionally, they ensured that each implementation strategy was documented and described. We applied these recommendations to the Expert Recommendations for Implementation Chance (ERIC) implementation strategies to further contextualize the strategies (14).

3 Results

Sixteen individuals (14 clinicians and 2 patients) were invited to participate in the workshop; however, 9 clinicians and 2 patients (n = 11 total) participated (68.8% response rate). Of the 14 clinicians invited for a follow-up interview, 10 (71.4% response rate) completed these member-checking interviews. See Table 1 for their details. Providers described numerous barriers to routinely conducting a diagnostic work-up for CA. Table 2 presents influences to timely work-up for CA that informed the expansion of the system map of care for CA. Participants also recommended implementation strategies to increase uptake of this evidence-based diagnostic protocol of bone scintigraphy and monoclonal protein testing for the early detection of CA. See Table 3 for the recommended strategies.

The research team organized the updated map into three phases of the patient care experience for CA: pre-clinical, symptomatic, and diagnostic evaluation. Implementation strategies are broadly grouped (e.g., clinical decision support tools and provider education). Figure 1 illustrates the final systems map for CA. In the map, the black arrows illustrate patients’ steps in receiving CA-related care; green dashed circles are the implementation strategies identified through this research; red arrows illustrate the implementation strategies' potential impact on the patient experience, and the blue arrow illustrates how a patient's individual factors may influence their medical journey. Table 4 provides a more detailed description of the individual implementation strategies that can help influence the eventual uptake of bone scintigraphy and monoclonal protein screening.

Figure 1

3.1 Pre-clinical stage: barriers and implementation strategies

Participants noted the lack of patient knowledge as a barrier naming characteristics in seeking care for CA symptoms, including general awareness of CA, knowledge of CA symptoms, health literacy, family history/genetic status [for those with family members with hereditary ATTR (hATTR)] and related risk perceptions for CA as impacting the likelihood that patients will act on concerning health information or facilitators to seeking care. Participants suggested multiple mechanisms to promote patient education as an implementation strategy to increase the number of patients with clinical risk factors who discuss testing for CA with their providers. (IS1 in Table 4). Educational materials could be disseminated via patient-directed advertising (including social media marketing), to help patients recognize CA-associated signs and symptoms and thereby increase the likelihood of seeking care (IS2). These materials can be distributed at places where older adults frequent and among communications they use [e.g., American Association of Retired Persons (AARP) newsletters]. Another recommendation was to have pharmacies distribute CA informational fliers to patients with heart failure, given their increased risk for the condition (IS3).

Participants noted that patients did not always share genetic risk information for ATTR with family members who may have inherited the same genetic mutation. For patients with hATTR, the lack of sharing genetic mutation and ATTR-CA risk information was a barrier for their first-degree relatives to seek early detection. Participants noted that patients with hATTR should be encouraged to share their genetic status with family members to facilitate cascade testing, testing all first-degree relatives to identify affected relatives (IS4). A suggested implementation strategy was to have genetic counselors working with hATTR patients draft a letter to patients' first-degree relatives (i.e., siblings and children) that the patient can then give them to encourage them to undergo genetic testing. Such a letter confirming the first-degree relative's genetic diagnosis can facilitate appropriate genetic test selection and provide documentation for health insurance companies to cover the costs of genetic testing (IS5).

3.2 Symptomatic evaluation: barriers and implementation strategies

Access to a complete patient history was noted as a barrier to reaching a diagnosis. Participants emphasized the importance of comprehensive history-taking with a physical examination to the symptomatic evaluation stage of care in the map, tasks often carried out by a patient's primary care provider. One participant emphasized the need to provide in-depth training on CA for clinicians who work with older adults, given the increased prevalence of CA in older adults (IS6). Clinicians treating non-cardiac “red flag” symptoms (e.g., bilateral carpal tunnel syndrome, spinal stenosis, bicep tendon rupture) may only diagnose and treat the symptoms rather than correctly identify the underlying disease. One participant recommended that patients with CA improve clinician awareness by meeting with clinicians who previously misdiagnosed their CA or treated their symptoms only to share their diagnosis in a strategy they called a “patient take-back” (IS7).

To overcome clinicians' lack of clinical suspicion for CA, participants recommended multiple methods for clinician training and education (e.g., offering CA-focused fellowships, hosting CME events, and presenting CA case studies to clinicians), outlined in Table 1 (IS8). Further, to prompt clinical suspicion of CA, participants recommended creating and posting clinician reminders, such as posters in clinical examination rooms, to prompt clinicians to consider amyloid as the cause of the patient's symptoms (IS9).

Participants discussed challenges and lack of experience in ordering and interpreting follow-up diagnostic tests, including electrocardiogram (EKG/ ECG), echocardiogram, and cardiac magnetic resonance imaging (MRI). Test results may indicate the need for additional CA testing. Barriers for clinicians interpreting these tests included recognizing characteristic features in the test results and noting the presence of other CA-related symptoms. In response to these challenges, participants described various clinical support tools to aid in the early detection of CA. Participants recommended creating patient registries that include clinical characteristics suggesting CA risk factors, such as electrocardiogram, echocardiogram, and cardiac MRI findings. These registries could utilize artificial intelligence (AI) to analyze patients' electronic health records (EHR) and imaging reports to identify at-risk patients (IS10). Such registries could be paired with alerts to prompt clinicians to order CA diagnostic tests (IS11). One cardiologist and CA expert recommended using clear language in imaging reports, such as explicitly writing “amyloid” in echocardiogram reports, to prompt clinician attention (IS12). The same clinician recommended using a clinical decision support tool to calculate the risk of a patient having ATTR-CA (IS13) (15). The clinician recommended its use to consider CA as a potential differential diagnosis. Another cardiologist described how her clinic had an “amyloid order set,” a comprehensive collection of medical assessments and referrals used to detect CA, which facilitated proper referral to specialists for diagnostic evaluation of CA (IS14).

The clinicians who treat the non-cardiac initial symptoms of CA could order tissue biopsies (e.g., spinal tissue from spinal stenosis, renal tissue from gastrointestinal disorders, tissue during carpal tunnel release) and routinely request Congo red staining for amyloid (IS15). Further, participants recommended that pathologists receive additional training to properly perform Congo red staining, as there are often errors in conducting the test and interpreting the results (IS16). Additionally, participants suggested that sonographers receive training in recognizing amyloid by incorporating strain speckle tracking into their echocardiographic workflow, which could improve recognition of the CA phenotype through characteristic strain patterns (IS17).

3.3 Diagnostic evaluation: barriers and implementation strategies

Participants described challenges, including a need for more specialized knowledge to carry out evidence-based practices in bone scintigraphy and monoclonal protein screening. Such challenges include the need for single-photon emission computed tomography (SPECT) (rather than only planar imaging), the need for standardized training (of nuclear medicine technologists) for bone scintigraphy procedures, and the need for better quality control for reporting and documenting the results. One participant noted the need for nuclear medicine-qualified physicians (including cardiologists) to interpret bone scintigraphy correctly. To overcome these challenges, participants recommended ensuring that all who interpret and review the scan results follow nuclear medicine guidelines, particularly the American Society of Nuclear Cardiology's Practice Points for ATTR-CA PYP imaging (IS18) (16). Additionally, one participant proposed a quality control process of measuring interrater reliability among those reviewing the scans, to ensure they (IS19).

3.4 Cross-cutting barriers and implementation strategies

Participants noted barriers to navigating a complex, fragmented healthcare system. At the healthcare system level, participants recommended that hospitals employ patient navigators, individuals who assist patients in navigating a complex healthcare system from CA early detection to diagnosis and treatment. (Roles of patient navigators often involve scheduling appointments, providing health education, following up with patients, identifying resources such as transportation or financial assistance, etc.) They noted that patient navigators help patients overcome gaps in timely care and follow-up (IS20). Additionally, they recommended linking at-risk individuals to patient advocacy groups, such as the amyloidosis support groups, to provide support for patients before and after receiving a CA diagnosis (IS21).

Participants described a need for multispecialty teams organized around caring for patients with CA. Another participant noted the need for clinicians to work in “medical villages” rather than “medical silos,” and highlighted the difficulty of making a diagnosis without coordinated patient information from the multiple providers who may be treating CA symptoms. In response, some participants recommended creating “amyloid teams,” assembling dedicated clinicians with additional training to screen for, identify, and treat CA (IS22). Participants also described uncertainty regarding where to refer patients they suspect have CA in their local community. They discussed creating a database of local clinicians who specialize in treating this disease (IS23).

4 Discussion

This research focuses on identifying distinct, interlinked implementation strategies spanning multiple phases of the patient care journey and carried out by various specialists in a complex, adaptive system. It moves beyond describing diagnostic algorithms that that lead to the early detection for CA (17). However, it is critical to note that observing such algorithms and implementing clinical pathways can lead to clinicians' increased recognition of ATTR-CA red flags (18). Other researchers found that implementing clinical pathways increased diagnosis for CA with reduced diagnostic delay and reduced CA severity at time of patients' diagnosis (19). By implementing and testing the strategies identified in the current research and using a systems science lens, patients are expected to receive more timely evaluation for ATTR-CA by completing the evidence-based diagnostic tests. This study highlights implementation strategies often employed in quality improvement initiatives, such as providing clinicians with appropriate education (20), clinical support tools (21), and coordinated care (22). It also validates CA-specific strategies, such as encouraging those at risk for hATTR to undergo genetic testing for an ATTR gene variant (23). Additionally, we identified new, unexpected implementation strategies, including patient “take-back,” conducting biopsies during orthopedic surgeries, training sonographers to recognize amyloid, and developing recommendations to improve the quality of nuclear scintigraphy imaging procedures and documentation.

4.1 Common implementation strategies

Concordant with past research, participants reported underdiagnosis or late diagnosis of CA due to a lack of recognition and a lack of clinical suspicion. For example, one study estimated that patients were diagnosed with CA two years after experiencing multiple (non-specific) symptoms and after seeing a minimum of five physicians (24). To prompt clinicians to consider CA, our participants described numerous educational strategies. One novel strategy is patient “take-back,” in which a CA patient with a delayed diagnosis would share their diagnostic experience with their original clinician, either in person or by letter. This strategy may empower patients and allow their clinicians to learn from them. This strategy appears unique because it is not described in the literature, and it supports other efforts to collect patient-reported experiences to reduce diagnostic errors in health systems (25).

Participants recommended clinical decision support tools to help clinicians detect CA early. Some participants recommended using new technologies and AI paired with patient registries to screen for CA. Such tools that utilize clinical characteristics (26), electrocardiogram (27), echocardiogram (28), and MRI data (29) are reported in the literature. Past research also reports on the utility of AI and machine learning techniques to examine electrocardiogram reports among patients with severe aortic stenosis (pre-transcatheter aortic valve replacement) to detect patients at higher risk for negative clinical outcomes with CA (30). However, a more recent study recommended using machine learning techniques with CT strain data to identify ATTR-CA among patients with severe aortic stenosis (31). Current research is exploring the clinical value of using AI along the disease spectrum (32).

Due to these varied presentations and the complexity of the disease, a recommended strategy was to create multidisciplinary amyloidosis care teams, which can more holistically and effectively guide a patient with CA throughout the entire patient care journey. Such teams have been employed in healthcare systems (e.g., Centers of Excellence), similar to the “heart team” required for hospitals performing transcatheter aortic valve replacement (TAVR) (33, 34). The recommendation to form such expert teams in CA highlights the need for established standards or consensus for what qualifies as a “qualified amyloid team.” We do not believe such a standard currently exists, although some researchers have proposed criteria (35). For healthcare clinicians not working with such expert teams, ta directory of clinicians in their community who treat amyloid can help clinicians identify other professionals with CA expertise who can effectively treat and manage patients with CA.

4.2 New implementation strategies

Although amyloid guidelines recommend screening all first-degree relatives of patients with hATTR (36) approximately 10 years before the proband was either symptomatic or diagnosed with ATTR-CA (37), we did not anticipate the importance of the patient and family factors (e.g., trust in genetic testing and willingness to undergo genetic testing) or the suggested communication strategy (e.g., test patients with CA for genetic mutations at the time of diagnosis and communicate outcomes to family members immediately) to improve the implementation of cascade testing (38). In one multi-center study, family members carrying the genetic variants who participated in cascade genetic screening had a 57% lower risk of mortality compared to probands (39). It is critical that first-degree relatives of the index patient (proband) undergo genetic testing for hATTR, especially because this form of CA affects younger patients (e.g., median age of diagnosis is 39 years) than other forms of CA (40). Additionally, the European Society of Cardiology Working Group on Myocardial & Pericardial Diseases recommended family members who test positive for the ATTR-CA genetic variants, but who are asymptomatic should continue screening for ATTR-CA via bone scintigraphy every three years to detect this condition at its earlier stages (41). Research evaluated these recommendations, and found that, in clinical practice, they performed well (42). We encourage future research to examine best practices and strategies (e.g., patient letters, emails, in-person communication, and clinician phone calls) for communicating CA genetic risk to family members and encouraging their genetic testing and counseling.

Clinicians recommended strategies directed at pathological diagnosis. One recommended strategy was to routinely perform tissue biopsies in patients undergoing surgery for CA “red flags” such as carpal tunnel syndrome and spinal stenosis (43). Although this strategy has been reported in the case of carpal tunnel release surgery, it is not yet the standard of care (44). If validated, then these strategies could represent a paradigm shift in the screening of pre-symptomatic individuals with carpal tunnel syndrome or spinal stenosis and require significant coordination among pathologists, surgical specialists, neurologists, and cardiologists. Another related and unanticipated strategy is to train pathologists to perform Congo red staining correctly, a vital recommendation given that Congo red staining is the initial test for pathologic samples suspected of amyloid (45). Clinicians must understand the limitations of this test (46) and perform it as accurately as possible. This potential performance gap underscores the importance of a systems approach in defining barriers to optimal amyloid diagnosis.

Regarding the quality of echocardiography, the recommendation to train sonographers in strain imaging underscores the importance of allied health professionals within the broader system of care supporting CA diagnosis. This recommendation is important because there is a relative dearth of research focusing on sonography education (47).

Study participants described the importance of high-quality bone scintigraphy and echocardiography imaging and the risk of misdiagnosis if performed incorrectly. Their recommendations for bone scintigraphy were consistent with professional society recommendations that emphasize the need for SPECT over planar imaging and a 2- to 3-hour time interval to avoid excess blood-pool activity (48). The importance of proficiency in bone scintigraphy imaging and interpretation is also linked to the strategy of clinician education. Another recommended strategy was to employ a double reading of bone scintigraphy results (49), in which two radiologists read the same results to improve accuracy. This is a potentially valuable strategy because the interobserver reproducibility of bone scintigraphy studies has not been well studied beyond high-volume amyloid centers (50).

As is evident from both Figure 1 and subject matter experts' repeated emphasis on a “team” and non-siloed approach, successful CA early detection and diagnosis depend on several healthcare system components working together, not on cardiology alone. Efforts at implementation should employ a systems science approach, using multi-level strategies that span multiple stages of a patient's journey (51). This approach contrasts with a reductionist, siloed approach, where workflows and individual implementation strategies are tested independently, ignoring the relationship between upstream and downstream components.

4.3 Limitations and considerations

First, the research team included clinicians who participated in both the design and data collection for this study. This may impact the interpretation of study results, compromising the internal validity of study findings. Another limitation of this study is the use of a convenient, purposive sample of patients and clinicians. However, this is appropriate for qualitative research that relies on expert feedback to explore challenges in healthcare delivery. Another limitation is that the healthcare professionals who participated in the study worked across different healthcare institutions and settings, which limits the internal validity of this system map but likely enhances the external validity of our findings. Some clinician participants worked in hospital systems with protocols and teams designated for caring for patients with CA. In contrast, others worked in community hospitals and clinics that treat CA patients but lack the same infrastructure and frequency of CA treatment as the Centers of Excellence. We believe that having providers representing a variety of healthcare settings is a unique strength of this study, as expert panels are often limited to tertiary or quaternary care centers. However, future research should consider incorporating additional perspectives from health system administrators, pharmaceutical scientists, and medical trainees, whose influence on referral logistics, prior authorization processes, and out-of-pocket expenses profoundly shapes the real-world feasibility of any proposed intervention that stems from this work. Another participant-related limitation is that all included patients were identified by a single expert cardiologist, which risks selection bias, as patients chosen by an expert at an amyloid Center of Excellence may not represent the broader population of delayed-diagnosis patients.

5 Conclusion

Despite the availability of evidence-based practice guidelines on diagnosing CA, this condition is often undetected, leading to excess morbidity and mortality. Barriers to CA diagnostic testing broadly relate to an uncoordinated, fragmented, complicated healthcare system and a non-specific multisystem disease, of which red flag symptoms mirror less fatal causes. Our research, one of the earliest efforts to map barriers and facilitators to CA diagnosis, identified 23 distinct implementation strategies that can be evaluated to enhance CA early detection through the evidence-based practice of bone scintigraphy with monoclonal protein testing. This area of medicine and research calls for implementation scientists to conduct multilevel interventions involving various clinicians, including, but not limited to, those working in cardiology, primary care, neurology, imaging, surgery, and genetic testing and counseling. Future research or implementation efforts should tailor the CA system map to a specific healthcare system before selecting implementation strategies and creating an implementation blueprint to increase the evidence-based CA early-detection strategy of bone scintigraphy with monoclonal protein testing.

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