Understanding the High Prevalence of Low-Prevalence Chronic Disease Combinations: Databases and Methods for Research

Final White Paper

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Contract # HHSP2333700IT
September 20, 2013

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Prepared for:
James Sorace, MD, MS
Michael Millman, PhD
Assistant Secretary for Planning and Evaluation
U.S. Department of Health & Human Services
200 Independence Ave. S.W.
Washington, DC 20201

Prepared by:
Michael E. Rezaee, MPH
Lisa LeRoy, MBA, PhD
Alan White, PhD
Emma Oppenheim
Ken Carlson
Melanie Wasserman, PhD
Abt Associates Inc.
55 Wheeler Street
Cambridge, MA 02138

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The information contained in this white paper was compiled by Abt Associates, Inc. under contract #HHSP2333700IT to the Assistant Secretary for Planning and Evaluation (ASPE) in September 2013. The findings and conclusions of this report are those of the authors and do not necessarily represent the views of ASPE or HHS.

 

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1. Executive Summary

Understanding how to better care for individuals with multiple chronic conditions (MCC) is a priority for the Department of Health and Human Services due to the growing cohort of people with MCC and the associated health care cost and quality of care implications. In recent decades health services research has focused on one disease at a time, or on highly prevalent co-occurring conditions, leaving a large gap in our knowledge about how to optimally treat individuals who have more than one chronic illness. Individuals living with MCC know firsthand the difficulty of navigating the health care system, the lack of coordination between different health care clinicians, the impact of illness on daily living, the toll on family and friends, and the impediments to maximizing quality of life, among other difficulties. For the numerous patients with rare combinations of multiple chronic conditions, the difficulties are exacerbated by having few peers to talk with and learn from, and few clinicians who are familiar with best treatment and options for their particular combination of conditions.

Current MCC research has focused primarily on studying the impact of high-prevalence diseases (i.e. hypertension, hyperlipidemia, diabetes, arthritis, etc.) in terms of patient outcomes, care utilization and cost. However, an understudied group comprises patients with less prevalent combinations of MCC. How the group may change over time as individuals acquire new chronic conditions, or certain conditions change in intensity, has not been well examined. There are many unique constellations of MCC; for example, a recent study of approximately 32 million Medicare beneficiaries found over 2,000,000 unique combinations of MCC (Sorace et al. 2011). The distribution of constellations of MCC results in a curve with a very “long tail” of complex patients that changes nationally over time. Sources and methods for studying the long tail and recommendations for future research on less prevalent MCC are the primary focus of our paper.

Our methods included a review of the peer-reviewed and grey literature, facilitating discussions of a Technical Advisory Group, and interviews with key informants. Most of the published studies examined a small number of high prevalence conditions ( e.g., hypertension, hyperlipidemia, ischemic heart disease, diabetes, arthritis) and almost none focused on low prevalence MCC. Claims data and large surveys are most appropriate for exploring rare combinations because of the small cell size for any one unique combination of conditions but are limited by code misspecification, upcoding to maximize reimbursement and poor demographic and socioeconomic variables in the case of claims, and recall bias and insufficient diagnostic detail in the case of surveys, as well as other limitations. The sheer volume of data needed to study the long tail distribution necessitates using a diagnostic grouping system. Of the 14 grouping systems we reviewed, the number of diagnostic groups ranged from 25 to 272 with 1080 subgroups. The number of diagnoses that are included determines the number of groups that can be studied. Grouping classifications are not well documented or explained by the researchers who utilize them. We found other methodological and analytical issues that complicate our ability to study MCC in general, and the long tail in particular. The paper serves as a resource for researchers interested in building the knowledgebase on MCC.

There is much to be learned about individuals who have less prevalent combinations of MCC and therefore many opportunities for future research, both substantive and methodological. We need to understand who comprises the long tail (including when looking at data other than Medicare claims), and better understand their demographic characteristics, cost patterns, and clusters of biologically related and unrelated conditions. Comparisons with similar populations in other countries will help shed light on treatment options. Self-management techniques and disease management for MCC combinations are critical to achieving improved quality of life, but we know little about those interventions in the low prevalence MCC population. Research methods need to be adapted and documented to help build the knowledge base about persons with MCC and lead to more valid, reliable findings. We need quality measures that take multiple illnesses into account, and much better research on the service utilization patterns in order to accurately attribute and address costs.

Finally, there is much to be learned from individuals who have less prevalent conditions of MCC: how they prioritize and manage their own illnesses, what outcomes are most important to them, where they obtain information, and how their conditions relate to one another. In the paper which follows we identify gaps in the current knowledge base, methodological constraints with existing analytical tools, and opportunities for future research to improve the care and lives of a growing, disadvantaged population.

2. Introduction

Individuals with multiple chronic conditions (MCC) represent a growing percentage of the population. Some chronic diseases commence at birth, while others occur later in life, and they may be caused by genetic, behavioral, environmental, or infectious factors. Chronic diseases may become acute at times, may impair functioning or may be asymptomatic. While estimates vary by data source and methodology, those from the following studies are illustrative: in 2006, 28% of the population had MCC and by 2010 this increased to about 32% (RWJF, 2000 & Abt Associates, 2013). In 2010, 14% of Medicare beneficiaries with 6+ chronic conditions accounted for 46% of total Medicare spending (CMS, 2012). As individuals age, they are more likely to acquire MCC, however the rate of comorbidities is also increasing in the under 65 years-of-age population. As a high need population, the MCC cohort represents a large percentage of healthcare service utilization and cost. For example, persons with disabilities (the vast majority of whom have multiple chronic conditions) make up only 15% of the United States Medicaid population, but account for 43% of nearly the $350 billion per year in expenditures nationwide (Kaiser Family Foundation, 2009 & CMS, 2011).

Research on multiple chronic conditions has been scant in recent decades but is growing as the affected population increases. Understandably, current MCC research has focused primarily on studying the impact of high-prevalence diseases (i.e., hypertension, hyperlipidemia, diabetes, arthritis, etc.) in terms of patient outcomes, care utilization and cost. However, an understudied group comprises patients with less prevalent combinations of MCC. How this group may change over time as individuals acquire new chronic conditions, or certain conditions change in intensity, has only recently been examined. Overall, there are many unique constellations of MCC; for example, a recent study of approximately 32 million Medicare beneficiaries found over 2,000,000 unique disease combinations (Sorace et al. 2011). The distribution of constellations of diseases results in a curve with a very “long tail” of complex patients. Exhibit 1 depicts the beginning of Medicare’s long tail distribution. Sources and methods for studying the long tail are the primary focus for this white paper.

Exhibit 1: The Beginning of Medicare’s Long Tail: Prevalence of Top 250 Disease Combinations

Constellations categorized as “rare” can result from combinations of common chronic conditions and/or less common or rare diseases. In other words, there are multiple pathways to becoming less prevalent (See Exhibit 2), and combining less prevalent combinations may account for as much as 79% of Medicare expenditures and 32% of beneficiaries (Sorace et al. 2011). Unique constellations are especially complex when multiple organ systems are involved and the combination of diseases, or treatments interact with one another. Developing treatment strategies for these complex patients is extremely difficult.

Exhibit 2: Multiple Chronic Condition Combination Types

MCC Types	Example
Rare or less prevalent Condition in Combination with a Rare Condition	Multiple sclerosis and schizophrenia
Rare or less prevalent Condition in Combination with a Moderately Common Condition	Multiple sclerosis and lung cancer
Rare Condition or less prevalent in Combination with Common Chronic Conditions	Multiple myeloma, hypertension and depression
Combinations of Moderately Common Chronic Conditions with Common Chronic Conditions	Breast cancer, COPD, and arthritis
Unique Combinations of Common Chronic Conditions	Hypertension, hyperlipidemia, chronic back pain, and depression

Acknowledging the “long tail” is important in interpreting the results of many types of healthcare studies. If the long tail is not accounted for, the following can potentially occur:

• Quality measures may show skewed calculations due to inaccurately classified individuals. For example, a person with type 2 diabetes and Alzheimer’s disease may not be a good candidate for tight glycemic control.
• Healthcare costs are inaccurately calculated. The patient with heart disease and MS may have all of their healthcare utilization and cost attributed to their heart disease when it is really a combination of the two or the majority of the cost is due to MS-related service utilization.
• Randomized controlled trials (RCTs) may be designed inappropriately, causing the results to not be generalizable to non-experimental settings. For example:
  • The patients enrolled in the trial do not represent the comorbidities present in the actual patient population.
  • Complex patients may have higher attrition compared to other patients (e.g., MCC patients fall out of a study arm).
  • Investigators do not necessarily randomize for complexity or check to see if randomization has been successful for patients who may have MCC.
  • Even if complex patients are involved in RCTs, patients with different patterns of complexity will likely be encountered in the future, which may limit the generalizability and long term implications of results.
• Disease management guidelines for a specific chronic disease may not work when combined together with other chronic conditions, and, in some cases, may contradict other guidelines (Boyd et al. 2005.)

Purpose of the Paper

The Assistant Secretary for Planning and Evaluation (APSE) Office of Science and Data Policy contracted Abt Associates to explore how the “long tail” of the MCC population can be appropriately studied. As a first step, ASPE wanted to identify and review the existing data sources that can be used to understand the population, and to describe relevant methodological research issues. The paper is intended to serve as a resource for investigators working on MCC by describing the strengths and limitations of currently available databases and methods. The information can help both researchers and stakeholders better understand and interpret research results, as well as consider what steps might be taken in the future to improve the knowledgebase on health care for MCC. Specifically, ASPE’s guiding study questions were as follows:

Study question #1 – What are the findings from MCC research related to prevalence and patterns of chronic disease combinations, health care utilization and cost, with particular attention to addressing less prevalent combinations of chronic conditions (i.e., the long tail)?

Study question #2 – What methodologies and analytic techniques have been used to study MCC? What are the potential limitations of these approaches in considering less prevalent combinations of MCC?

Study question #3 – What data systems and data sets exist that can be analyzed to better improve HHS’s understanding of and approaches to addressing numerous less prevalent combinations of chronic conditions?

Study question #4 – What combinations of less prevalent combinations of chronic comorbidities are most critical to address in terms of care utilization and cost? What are the future research considerations for MCC research?

In the Background section of the paper (Section 4) we describe why less prevalent MCC are an important area of study, as well as address the definitional problems and the interests of various stakeholders in MCC research. We describe the data collection and analysis methods we have used in Section 5: (1) literature review, (2) Technical Advisory Group, (3) key informant interviews, and (4) datasets and grouping systems. In Section 6, we characterize the literature on prevalence and patterns of MCC that has been conducted to-date. Methodological and analytic considerations of MCC research, such as grouping systems and study designs, are discussed in Section 7. Section 8 contains a review of potential datasets for MCC research. Section 9 discusses consideration for future areas of inquiry.

3. Background

The Context for Studying the Long Tail of Low-Prevalence Combinations

Clinical research has focused on single chronic disease conditions for decades. For many reasons, researchers have focused on understanding one medical condition at a time. Although especially true for clinical trials due to the need to reduce confounders and increase the strength of evidence, there is growing recognition of the limitations of this approach. As pointed out in a recent article by Tinetti and colleagues (2012) in the Journal of the American Medical Association, United States payment systems, service delivery, clinical decision making, and quality measurement have all been designed around single diseases. Until very recently, clinicians were paid according to individual diagnoses; in addition, many practitioners treat their patients according to guidelines and practices for a specific disease because guidelines for MCC do not exist in clinical practice. Paradoxically, however, most individuals with a chronic disease have more than one condition, and the group of individuals with MCC is growing.

Two thirds of healthcare spending is for multimorbid individuals over age 65 (Anderson, 2010). Boyd and colleagues (2005) examined the consequences of applying single disease guidelines to a hypothetical 79-year old woman with osteoporosis, osteoarthritis, type II diabetes mellitus, hypertension and chronic obstructive pulmonary disease, all of moderate severity. The results of these multiple guidelines for single conditions resulted in the patient being prescribed 12 medications requiring 19 doses per day, 14 non-pharmacological activities (e.g., nutrition), one-time education and rehabilitation interventions, and daily to biennial monitoring of chronic conditions requiring at least 2 to 4 primary care visits and 1 ophthalmology visit per year. In addition, there was potential for medication contraindications. The regime is not only impractical, it would result in potential risks, lack of care coordination, and burden on the patient and caregivers. In order for the United States health care system—particularly Medicare—to be successful, it must adapt to meet the needs of specific patients with MCC and their providers. To do so, accelerated knowledge and research about MCC is needed by policy-makers and healthcare providers.

There is extensive research on the most common chronic conditions in the Medicare population: hypertension, hyperlipidemia, ischemic heart disease, diabetes, arthritis, heart failure, depression, chronic kidney disease, osteoporosis, Alzheimer’s disease, etc.; and extensive research on these conditions in conjunction with a specific co-occurring chronic condition (for example hypertension and depression, or diabetes and chronic obstructive pulmonary disease); but very little research on low-prevalence MCC (CMS, 2011).

 

Definitions of Multiple Chronic Conditions

One of the difficulties in studying multiple chronic conditions is the lack of a clear definition of the phenomenon. For example, the official definitions in Exhibit 3 below, created by three organizations, are similar but not the same. A recent paper by Goodman and colleagues provides a robust discussion of definitional issues related to multiple chronic conditions and elaborates the many different definitions being used in different contexts by different stakeholders (Goodman, et al., 2013). In addition, the authors offer a conceptual model for classifying chronic conditions and call for a collaborative process to begin to standardize and systemize definitions and set of conditions that are important for clinical practice, research and policy making.

Exhibit 3: Definitions of Multiple Chronic Conditions by Three Organizations

Organization	Definition of Multiple Chronic Conditions
HHS Assistant Secretary for Health	Chronic conditions are conditions that last a year or more and require ongoing medical attention and/or limit activities of daily living. They include both physical conditions such as arthritis, cancer, and HIV infection. Also included are mental and cognitive disorders, such as ongoing depression, substance addiction, and dementia. MCC are concurrent chronic conditions. In other words, multiple chronic conditions are two or more chronic conditions that affect a person at the same time. For example, either a person with arthritis and hypertension or a person with heart disease and depression, both have multiple chronic conditions (DHHS 2013).
National Quality Forum	Two or more concurrent chronic conditions that collectively have an adverse effect on health status, function, or quality of life, and that require complex healthcare management, decision-making, or coordination (NQF 2012).
Institute for Medicine	Definition: Long-term health conditions that threaten well-being and function in an episodic, continuous, or progressive way over many years of life (IOM 2012).

In a study of Medicare patients, Fortin and his colleagues (2012) concluded that the lack of uniformity in definition results in dramatically different prevalence estimates. Because there are numerous different constellations of MCC (particularly low prevalence MCC), researchers have used simple counts of the number of conditions an individual has as a measure of intensity or comparison. Although the specific conditions that are included differ by study, reporting only the number of MCC can lead to inconsistent conclusions and lack of comparability (Fortin et al. 2012 & Salive, 2013). Individuals with MCC are often defined as “complex patients,” which is both a physiological description that encompasses the complexity of having more than one condition as well as a characterization of their interface with the health care system—which is complicated by multiple conditions (Rich et al., 2012, Safford et al., 2007, & Grant et al., 2011).

Consensus-building efforts may in the future help to refine the definition of MCC used by researchers. In the meantime, given the sparse literature, we examined all papers related to multiple chronic conditions reagardless of the definition used by the authors.

Federal Initiatives on Multiple Chronic Conditions

The need to better understand how to care for individuals with multiple chronic conditions is a priority for the Department of Health and Human Services because of the growing size of the MCC cohort and the associated health care cost implications. In 2008, the HHS Office of the Assistant Secretary for Health launched an initiative to strengthen efforts directed at MCC, including establishment of the HHS Interagency Workgroup on MCC (Parekh et al., 2011). The Workgroup included representatives from key HHS Operating Divisions and Offices and was charged with identifying gaps in research and health care services for individuals with MCC. The Workgroup developed the HHS Strategic Framework on MCC (DHHS, 2010), a national roadmap for public and private stakeholders, and also produced and disseminated an annotated inventory of initiatives involving MCC. The Strategic Framework, published in December 2010, has four major goals:

1. Fostering health care and public health system changes to improve the health of individuals with MCC.
2. Maximizing the use of proven self-care management and other services by individuals with MCC.
3. Providing better tools and information to health care, public health, and social services workers who deliver care to individuals with MCC.
4. Facilitating research to fill knowledge gaps about, and interventions and systems to benefit, individuals with MCC.

For each goal there are subsets of objectives and action strategies for HHS, healthcare providers, and other stakeholders. The updated inventory of HHS MCC-related activities, programs, and initiatives, released in 2011, contains information on over 100 projects and studies organized according to the four goals, with web links for users (DHHS, 2011). The MCC Strategic Framework has helped to focus and align the activities of HHS agencies, and many agencies have initiatives that contribute to the four goals. It is important to note that there are a number of important research initiatives and collaborations currently underway that will produce findings and new analytic methods that will greatly shape MCC research moving forward. For example, the Agency for Healthcare Research and Quality’s (AHRQ) created the MCC Research Network, a collaborative of researchers from across the country conducting foundational research to improve our understanding of how to best study and treat MCC patients (AHRQ, 2013). The network includes 45 research teams with grants as follows:

• Eighteen exploratory and developmental R21 grants funded in 2008 to address the gaps in knowledge related to MCC patients and preventive services.
• Thirteen infrastructure development R24 grants funded in 2010 to develop new databases and information systems study MCC patients.
• Fourteen exploratory R21 grants funding in 2010 to conduct comparative effectiveness research using currently available data.

Although we do not focus on the current federal initiatives in-progress, the methodological challenges and considerations discussed in the white paper can be applied to all types of MCC research, including both past and future efforts.

Stakeholder Perspectives

It is important to note that the significance of examining less prevalent, or rare, MCC combinations depends on the perspective of the stakeholder, which ranges from the patient to the provider to the health plan risk adjuster. A clinician trying to assess the best course of treatment for a patient has different information needs than does a health insurer that is attempting to reduce health care costs, or a state chronic disease director who wants to reduce chronic disease burden for a population of people. The level of detail needed about multiple chronic conditions at the individual level—and therefore the importance of the long tail—will vary according to stakeholders’ goals. Similarly, where research is concerned, the number of diagnostic codes needed to categorize individuals with multiple chronic conditions depends on the perspective of the information users. However, from the patient’s perspective, every condition and every diagnosis matters.

There are small numbers of patients in many, many combinations of MCC (Sorace et al., 2011) and any one provider or health plan may have extremely few patients with a specific combination of conditions. For a clinician the specific constellation of MCC is critical in determining what the best possible treatment is, but studies on small, unique sets of people with MCC are rare. Likewise, a person with a less prevalent combination of MCC may have difficulty finding information on how to best manage their personal conditions.

Policy makers are faced with a challenge because there is a lack of evidence on treatment for low-prevalence MCC and it is not clear at what level in the health care system interventions can be effective, or how transferable interventions are from one patient population to another. Demonstration projects, natural experiments and research studies can all contribute to new learning.

In the table below, we identify groups with a stake in multiple chronic conditions research and list their primary interests (See Exhibit 4). The degree to which stakeholders see value in studying less prevalent MCC is a matter of perspective and purpose. Similarly, the research aims will differ by stakeholder.

Exhibit 4: MCC Research Stakeholder Perspectives

Stakeholder	Interest in Multiple Chronic Conditions Research
Clinicians	Inform the treatment of specific patients Practice guidelines Clinical decision support New models of healthcare delivery developed from MCC research
Policymakers	Quality measures for healthcare for patients with MCC Cost effectiveness research of policy interventions and new payment models addressing patients with MCC Research and policy agendas addressing MCC
Public Health Officials	Studies of disease prevalence and patterns Development and evaluation of preventive services and public education campaigns Development of guidelines for dissemination Development of population measures for surveillance
Risk Adjusters	Detailed clinical and demographic health information
Provider Organizations/ Systems	Quality measures for healthcare for complex patients Comparative effectiveness analyses of treatments Cost of care for complex patients Development of benchmarks for system dashboards
Financing Entities	Prevalence and cost of treating patients with specific chronic conditions Identification of populations that account for the greatest costs Identification of care systems or other healthcare innovations that successfully lower costs of treating complex patients
Patients	Care management and self-management Symptom reduction and maximizing quality of life Medication management Out of pocket costs Quality of care/patient-centered care for all conditions
Researchers	Methods for studying MCC patients Implications for RCT designs Consistent measures of chronic conditions Developing models for health system design improvement
Federal Demonstrations	Prevalence and cost of treating high-cost, complex patients Impact of large-scale programs to improve self-management and decrease costs among complex patients.

The patient perspective was illuminated through discussion with a representative of “Patients Like Me,” a company that encourages individuals to share their medical and treatment information on a web platform, and to connect with other people who are also willing to share. The company initially invited consumers to identify themselves with a primary disease (like ALS) as they were promoting sharing by individuals with the same medical condition. However, the participants typically listed more than one condition in their profiles. After a number of years, the company opened the platform to allow participants to label their own medical conditions, and to choose which one was their “primary” condition rather than offering only pre-determined categories. Due to this expanded patient input, the number of medical conditions included on the website grew from 300 to 2,000 as people wanted more specific and discrete disease categories by which to identify themselves and their peers.¹

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¹ Personal communication with Sally Okun, RN, MMHS, VP of Advocacy, Policy & Patient Safety at PatientsLikeMe.

4. Methods

Our methods for addressing the four research questions included a review of the peer-reviewed and grey literature, convening a Technical Advisory Group, and interviewing key informants.

Abt Associates conducted a review of the peer-reviewed and grey literature related to prevalence of MCC, disease combinations, diagnosis coding, and databases and analytic techniques that have been used to conduct chronic disease research. Our detailed MEDLINE search strategy can be found in Appendix A. The purpose of the literature review was to identify MCC research studies and methods papers on multimorbidity research. Studies that focused on individual chronic diseases were excluded from the review. The results of the review are found in Sections 6 and 7 of the white paper.

To advise the project, Abt Associates and ASPE organized a Technical Advisory Group (TAG), which was comprised of MCC experts from a variety of different HHS agencies. A list of the TAG members and their affiliations is contained in Appendix D. On December 18^th, 2012, Abt and ASPE conducted an in-person meeting with the TAG. The objectives of the meeting were:

1. To discuss the initial findings from literature and database reviews related to less prevalent combinations of MCC, as well as the search strategy itself.
2. To generate a list of potential databases and methods that could be used to study less prevalent combinations of chronic conditions, and to discuss the challenges and limitations of these approaches.
3. To identify additional peer-reviewed articles and grey literature, and databases that were relevant for the project.

During the meeting, TAG members provided insightful comments and feedback that were later directly incorporated in the study. On May 10^th, 2013, the TAG was convened for a second meeting to review and provide edits and suggestions on the first complete draft of the white paper, that were later incorporated.

To further inform study of the long tail, Abt and ASPE conducted key informant interviews with seven individuals representing various stakeholder perspectives. A list of key informants can found be found in Appendix E. Each of the individuals was asked to share his or her perspective and knowledge regarding MCC research, studying less prevalent combinations of MCC, and priorities for MCC research moving forward. The information gleaned from key informants is integrated throughout the report.

Additionally, Abt Associates conducted a detailed review of 17 databases that may potentially be used for MCC research on less prevalent MCC, as well as 14 diagnosis grouping systems that can be used to categorize diagnosis information for MCC research. A more detailed description of these reviews can be found in Sections 7 and 8.

5. Characterizing the MCC Literature on Prevalence and Patterns of Chronic Disease Combinations (Study Question #1)

What are the findings from MCC research related to prevalence and patterns of chronic disease combinations, health care utilization and cost, with particular attention to addressing less prevalent combinations of chronic conditions (i.e., the long tail)?

For decades, chronic disease research has focused on studying prevalence, patterns, and the health and healthcare impacts of individual chronic conditions. However, the field of chronic disease research is currently evolving from a single disease focus to a paradigm that places emphasis on the importance of studying multiple chronic conditions (MCC). The shift in priorities is due to growing awareness of the compounding impacts of MCC on patients’ health, the United States healthcare system and society. As a result, MCC patients are becoming a focus of chronic disease researchers and are being targeted by providers and health plans for intervention.

Below we characterize the research that has been conducted on MCC to date. Based on the findings from the literature review, key informant interviews, and TAG meetings, we summarized MCC research according to three broad topic areas:

• Prevalent combinations of MCC
• Chronic condition clusters and co-occurring conditions
• Less prevalent combinations of MCC

We provide a brief introduction to each of these research areas and describe some of the findings that have been published to date.

Prevalent Combinations of MCC

In the United States, much of the research on multiple chronic conditions focuses on highly prevalent conditions ( e.g., obesity, hypertension, and diabetes) because they affect a large number of individuals, may be successfully managed or controlled, and they are included in major national surveys and other data collection efforts. The purpose of the literature was two-fold: 1) to characterize the burden of MCC across various populations, and 2) to identify MCC populations associated with increased healthcare utilization and poorer quality of care, so that patients can be targeted for intervention by providers, health plans and public health officials.

To conduct the work, researchers have employed methods such as basic prevalence and incidence calculations, and regression modeling and odds ratios to predict healthcare utilization and cost based on either the occurrence of MCC or the number of MCC a patient has. MCC prevalence has commonly been measured as the percent of patients in a population with two or more chronic conditions, while chronic disease complexity has been assessed through examining the distribution of MCC patients across an increasing number of chronic conditions ( e.g., 2, 3, 4, 5 + conditions). Predictive statistics are then used to estimate healthcare utilization, cost and quality of care based on the occurrence of MCC or the number of MCC for a specific patient.

A number of studies and initiatives have investigated both the prevalence and complexity of MCC across a variety of different populations (See Exhibit 5). One of the most well-known is the CMS Chronic Conditions Data Warehouse (CCW), which not only provides a database of patients with chronic conditions for research purposes, but also an interactive dashboard to investigate chronic condition prevalence, condition counts, and utilization information using a variety of different demographic filters ( e.g., gender, geographic area, and dual eligibility status). Information contained in the CCW database originates from Medicare and Medicaid beneficiary claims and assessment data from different healthcare settings across the continuum of care (CMS, 2013). By using the dashboard (which can be applied to Medicare fee-for-service beneficiaries only), users can compare prevalence estimates between states or between a state and national benchmarks. As an example, 37% of Medicare beneficiaries in New Hampshire have five or more chronic conditions, compared to 41% in Alabama and 43% nationwide.

The Faces of Medicaid publications have articulated the prevalence of MCC among Medicaid beneficiaries. The 2007 publication The Faces of Medicaid II: Recognizing Needs of People with Multiple Chronic Conditions estimated that 10% of non-disabled, adult Medicaid beneficiaries had three or more chronic condition categories, compared to 35% of adults with a disability and 39% of elderly Medicaid beneficiaries (Kronick et al., 2007). Similarly, in 2012 the National Center for Health Statistics reported that 21% of non-elderly, United States adult civilians have two or more chronic conditions, and that the rate of MCC in populations is increasing over time (Fried et al., 2012). As shown in Exhibit 5 below, prevalence estimates differ by study, depending on the population being studied, the number of chronic conditions per person included in the study, and the number of combinations of MCC.

Exhibit 5: Comparison of MCC Prevalence Estimates by Study; for Over and Under Age 65

When studying MCC prevalence among Veteran Affairs (VA) patients, Yu and colleagues found that 52% of VA patients had two or more chronic conditions. Of that number, 17% of patients had two chronic conditions, while 35% had three or more (Yu et al. 2003). Similarly, Steinman and colleagues found that approximately 90% of elderly VA patients had three or more chronic conditions; 44% has three to five chronic conditions, while 32% and 14% had six to eight and greater than eight conditions, respectively (Steinman et al. 2012). These prevalence estimates are considerably higher than the 21% that has been reported for all Americans (Vogeli et al., 2007), but demonstrate that MCC are more prevalent within certain populations and increasing age groups. The studies listed in Exhibit 5 have been stratified by average patient population age (less than or greater than or equal to 65 years) to demonstrate the effect of age on MCC prevalence calculations.

As shown in Exhibit 5 prevalence estimates ranged from 14% in Canadian civilians to 93% in Swedish adult in-hospital patients. Although patient population and setting play important roles in determining prevalence, utilizing different methods and analytic techniques can also lead to inconsistent estimations. Researchers used anywhere from nine to 260 chronic conditions categories to study prevalence and the occurrence of one to fourteen chronic conditions to examine different depths of chronic disease complexity. Various data sources and diagnosis code grouping systems were also used.

Just as MCC prevalence is associated with patient age, it has been well documented that healthcare expenditures are positively associated with an increasing number of MCC (Lehnert et al., 2011). In the study by Yu and colleagues 73% of total costs to the VA healthcare system were found to be attributable to patients with three or more chronic conditions, while only 13% and 9% of costs could be attributed to patients with two or a single chronic condition, respectively (Yu et al. 2003). Likewise, in a study of working-age self-funded health plan enrollees, mean annual cost of MCC increased from $4,442 for patients with one chronic condition to over $23,000 for patients with five or more MCC (Naessens et al., 2011). A similar relationship between MCC and cost has also been observed with regard to out-of-pocket medical expenditures (Schoenberg et al., 2007).

MCC are also associated with increased healthcare utilization and mortality as well as poorer quality of life for patients. In a cross-sectional study of Medicare fee-for-service beneficiaries, Wolff and colleagues found a positive relationship between inpatient admissions and hospitalizations and the number of chronic conditions a patient had (Wolff et al., 2002). Similarly, Glynn and colleagues found a strong association between an increasing number of chronic conditions and the frequency of primary care consultations, hospital admissions and hospital out-patient visits among primary care patients (Glynn et al., 2011). With regard to mortality, research suggests that patients with MCC have higher mortality rates compared to patients without chronic conditions. Lee and colleagues found that the five year mortality rate for patients without chronic conditions (4%) was considerably lower than for patients with one (6%), two (8%), three (11%) or four or more (17%) diseases (Lee et al 2007). Lastly, patients with MCC are known to more frequently report limitations in daily living/instrumental activities and “fair” or “poor” overall health status compared to patients without MCC (Chen et al., 2011 & Gulley et al., 2011). However, arguments have been made that patients with a large number of MCC may actually receive higher quality care than patients with fewer conditions due to the increased number of physician visits these patients make (Bae & Rosenthal, 2008).

Overall, the majority of MCC research conducted to-date describes prevalence and complexity of multimorbidity, as well as the relationships that exist between MCC and healthcare utilization, cost and other related metrics. Findings demonstrate that MCC are common across all populations, but are concentrated in specific patient populations and age groups (e.g., the elderly, disabled and VA patients). Furthermore, MCC are associated with increased healthcare utilization, costs, and mortality, as well as lower quality of life. Finally, MCC research in the United States has primarily been conducted on chronic conditions that are highly prevalent and well-known; low-prevalence conditions have not been well studied.

Chronic Condition Clusters and Co-occurring Conditions

Research on chronic condition clusters and conditions that co-occur with a primary or “index” disease is increasing and leading to understanding of patterns of chronic disease combinations and how MCC co-occur or spread across populations in clinically and statistically meaningful ways. Knowing which chronic diseases tend to co-occur together and manifest over time offers clinicians the ability to develop multi-disease clinical guidelines and to identify opportunities for longitudinal disease prevention for patients. Conditions that co-occur may be statistically associated with one another with no known causal relationship or have an underlying pathophysiological connection (van den Akker et al., 1998). Although more research may be warranted to further investigate non-causal disease relationships, understanding which chronic conditions tend to cluster together provides clinicians with the opportunity to more accurately target disease prevention efforts and understand multimorbid complexity on a more granular scale. Metabolic syndrome is an example of a cluster that is widely recognized in the United States as well as internationally.

Two methodological approaches have been used to study patterns of chronic disease combinations and MCC co-existence. The more simplistic of these two approaches is to calculate the most common dyads and triads of co-occurring chronic conditions by determining what chronic conditions co-occur with an index disease, or by simply examining the percentage of patients in a population with a given combination of chronic diseases (Marengoni et al., 2009). For example, Lochner and colleagues found that hypertension and hyperlipidemia was the most common dyad among Medicare patients of all age groups (Lochner et al., 2013) while diabetes, hypertension, and hyperlipidemia was the most prevalent triad among younger Medicare patients, and ischemic heart disease, hypertensions, and hyperlipidemia, and arthritis, hypertension, and hyperlipidemia were the most common triads among older Medicare patients. As shown in Exhibit 6, a number of different dyads and triads have been reported in the literature to-date. Most studies report two-way and three-way combinations that include chronic diseases such as hypertension, hyperlipidemia, heart disease, diabetes and arthritis. Low-prevalence chronic disease combinations have not been included within reported dyads and triads.

Exhibit 6: Research on Co-occurring Chronic Condition Dyads and Triads

The second methodological approach that has been used to study patterns of chronic disease combinations and MCC is cluster analysis. Cluster analysis is a type of statistical approach that groups relatively homogenous or similar patients into clinically relevant groupings based on calculated correlations between diagnoses. Cluster analysis is a relatively “novel” statistical method and as a result, specific methods employed vary significantly across studies. For example, researchers have used techniques such as agglomerative hierarchical clustering, factor analysis, and multiple correspondence analysis, among other approaches, to examine correlations between diagnoses. The variability in these approaches makes it difficult to interpret chronic condition clustering research, as differences in analytic approach may influence results.

The number of chronic disease clusters vary by study, reporting anywhere from three to thirty clinically significant chronic disease clusters or patterns that warrant attention or further investigation (Schafer et al. 2010 & Steinman et al., 2012). In a study by Prados-Terros and colleagues, five patterns of chronic disease clustering were observed in a primary care population: cardio-metabolic, psychiatric-substance abuse, mechanical-obesity-thyroidal, psychogeriatric, and depressive disorders (Prados-Torres et al., 2012). Similarly, John and colleagues found four clusters among a rural community-dwelling population which included cardiopulmonary, sensory-motor, depressive and arthritic disorders (John et al., 2003). As shown in Exhibit 7, the majority of chronic condition clusters include diagnoses related to cardiovascular, metabolic, neurological and mental health conditions, which are common conditions. Low-prevalence chronic disease combinations that would be found in the “long tail” have not been reported as outputs of cluster analysis studies to-date.

To-date studies on chronic condition clusters have primarily been conducted outside of the United States, in countries such as Sweden, Spain and Germany. The international tendency speaks to the quality and granularity of data available in the United States compared to other countries. European countries in-particular have more standardized and robust healthcare data infrastructures compared to the United States (OECD, 2013).

Exhibit 7: MCC Research Studies Using Cluster Analysis by Author

Although chronic condition clustering and co-occurring conditions research is relatively new, it is a promising means by which to study patterns of chronic disease combinations and the full complexity of disease in various populations. However, the variability in analytic methods used to study co-existing MCC (e.g., dyads, triads, cluster analysis) make the results of these studies difficult to interpret and generalize to other populations. Also, clustering research has primarily been conducted on chronic conditions that are prevalent and/or aggregated into large groups (e.g., all cancers and mental illness); studies have not reported “long tail” distributions of potential disease clusters.

Less Prevalent Combinations of MCC

Little MCC research has focused on studying the numerous less prevalent combinations of MCC. However, two recent studies have addressed how less prevalent chronic disease combinations are cumulatively associated with healthcare costs. Sorace and colleagues used the Hierarchical Condition Categories (HCC) model to group conditions and found that Medicare beneficiaries could be classified into three distinct groups according to their chronic condition combinations: 1) patients who didn’t have chronic conditions as defined by the HCC model, 2) patients belonging to the 100 most prevalent chronic disease combinations, and 3) patients belonging to the remaining two million possible disease combination categories (Sorace et al., 2011). They found that approximately one-third of beneficiaries could be classified into each group, but that 79% of expenditures were associated with the third group of beneficiaries who had one of two million possible disease combinations. The authors concluded that the majority of Medicare expenditures can be attributed to a complex group of patients with less prevalent combinations of MCC; this results in a “long tail” distribution as displayed in Exhibit 8. In interpreting Exhibit 8, the reader should note that as there are over 2 million disease combinations calculated by this methodology, the figure’s X-axis would need to be extended over 8,000 fold to the reader’s right before both the expenditure and the population cumulative lines reached 100%. A follow-up study confirmed this complexity and found that national distribution of disease combinations changed over time (Sorace et al., 2013).

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Exhibit 8: Percent of Disease Prevalence and Cost in the Beginning of Medicare’s Long Tail

Note on the Exhibit: The exhibit displays the first 250 Disease Combinations (ranked by prevalence) from the baseline HCC analysis as calculated by Sorace and colleagues (Sorace et al. 2011). Chronic disease combination classifications ( e.g., high, moderate and low) represent rough approximations; specific criteria for each classification have not been defined. Note that the left Y-axis represents the proportion of the population that is included in each unique disease combination, and is adjusted for the 32% of beneficiaries and 6% of expenditures that are associated with the no-MCC population. The right Y-axis represents the cumulative percent of the total population (red format) and the total expenditure (blue format). Note that approximately 75% of expenditures are associated with the 27% of patients that are not represented by the most prevalent 250 disease combinations. As there are over 2 million disease combinations calculated by this methodology, the figure’s X-axis would need to be extended over 8,000 fold to the reader’s right before both cumulative lines reached 100%.

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There are two important concepts to be gleaned from these findings. First, the issue of “small cell size” limits the ability to intervene on or study a substantial number of patients with similar diagnoses. For example, given that approximately 65% of the over 32,000,000 beneficiaries studied had one of over 2,000,000 disease combinations the average cell size for a disease combination is in the range of 10 to 11 beneficiaries nationally.

The second important concept that can be learned from Sorace and colleagues is that healthcare costs for MCC patients with low-prevalence chronic disease combinations are significantly higher than those costs for patients with high prevalence combinations. As can be seen from Exhibit 8 approximately 75% expenditures are associated with the 27% of patients that are not represented by the most prevalent 250 disease combinations. To effectively address healthcare costs associated with MCC patients, efforts focused on patients with low-prevalence disease combinations must also be considered.

Finally it is important to note that the degree of complexity presented in Exhibit 8 is based on the observed frequency of disease combination phenotypes alone and does not include demographic traits ( e.g., sex, age, and race) or biological variables such as genomic variation. These additional variables may also be important in a given individuals health care plan.

Overall, research on less prevalent combinations of MCC represents a change in thinking from studying highly prevalent chronic diseases to understanding chronic disease complexity at a much more granular level ( e.g., the “long tail” distribution). Although other researchers have verbally confirmed similar research findings, Sorace and colleague’s work remains the only published literature on low-prevalence combinations of MCC the authors are aware of to-date. In the sections that follow, methodological considerations for MCC research are discussed with a special emphasis on the implications for conducting research on low-prevalence combinations of MCC.

6. Methodologies and Analytic Techniques (Study Question #2)

What methodologies and analytic techniques have been used to study MCC? What are the potential limitations of these approaches in considering less prevalent combinations of MCC?

In the section below we discuss the methodological and analytic concepts to consider when conducting MCC research, with a special emphasis on less prevalent combinations of chronic conditions. We discuss the methodologies and analytic techniques that have been used to conduct MCC research to-date, the potential strengths and limitations of these approaches and how they relate to studying less prevalent combinations of MCC.

Defining Diagnosis of Chronic Condition

There are two main sources of information about patients’ chronic conditions: 1) surveys that collect self-reported disease status, and 2) claims and clinical systems that contain diagnosis codes (e.g., International Classification of Disease, 9^th edition [ICD-9], ICD-10, Systematized Nomenclature of Medicine Clinical Terms [SNOMED CT]). Other sources of information, such as pharmaceutical prescription or laboratory data, can also be used to identify patients’ chronic conditions. However, these additional modalities are not thoroughly discussed in this paper.

MCC research has been conducted using both primary sources of diagnostic information noted above. For example, Schoenberg and colleagues analyzed Health and Retirement Study (HRS) data to understand the relationship between chronic disease constellations and out-of-pocket medical expenditures. In the study, chronic conditions were identified using eight self-reported chronic conditions from the HRS (Schoenberg et al. 2008). Similarly, Bae and Rosenthal used 177 ICD-9 codes derived from self-reported chronic conditions from the Medical Expenditure Panel Survey to study MCC and quality of care (Bae & Rosenthal, 2008). Conversely, Sorace et al., used approximately 3,000 ICD-9 codes derived from the HCC model to study the complexity of disease combinations in the Medicare population (Sorace et al., 2011).

There are strengths and weaknesses of self-reported versus claims-based information for identifying chronic conditions (See Exhibit 9). Claims-based diagnosis codes allow researchers to study a large number of chronic conditions at a very fine level of granularity and to understand the full range of patients’ diagnoses, including which specific diagnoses are present ( e.g., primary malignant neoplasm of the lung or carcinoma in situ of the lung vs. simply lung cancer). Sensitivity is critically important in enabling the study of less prevalent or rare chronic disease combinations. Claims are usually provider-generated and based on a differential diagnosis and supporting clinical documentation, eliminating potential error associated with patient self-reported information and other survey-related biases, such as recall and selection concerns. However, there are systematic limitations associated with ICD-9 codes, such as misspecifications, unbundling, and upcoding by providers and coders (O’Mailley et al., 2005). There is also a tendency for providers and billers to under-report diagnoses that lack payment incentive, such as mental health conditions. These issues can lead to inaccurate estimates of chronic disease prevalence and imprudent results. Diagnosis coding using ICD-9 and ICD-10 codes has also been shown to misestimate the prevalence of certain conditions.

Exhibit 9: Strengths and Weaknesses of Self-Reported versus Claims-Based Chronic Conditions

Coding Type	Strengths	Limitations
Self-Report	Easy to collect, used to identify prevalent conditions, patient-derived.	Subject to recall, sampling and selection bias. Few diagnoses studied and at a coarse level of granularity. Limited number of patients surveyed/studied.
ICD-9	A large number of diagnoses are considered at a fine level of granularity. Commonly used in the United States. Used in large administrative databases; large sample size.	There are a number of well documented limitations, such as over and underestimation of certain diseases, as well as inaccuracies due to malicious coding behavior
ICD-10	Associated with improved coding accuracy. Greater number of diagnoses considered and at a more granular level. Used in large administrative databases; large sample size.	Not in widespread use in the United States and won’t be for a number of years. Limited research available on coding inaccuracies and other shortcomings.
SNOMED CT	Greatest number of diagnosis codes considered at the finest level of granularity.	Limited research available on coding inaccuracies and other shortcomings. Potentially too granular for use in certain healthcare settings.

Underestimation is a concern when a significant proportion of the population may not have a claim during the study period; overestimation may occur for conditions that lead to higher payment rates if they are reported as being present. Woo et al. found that obesity identified by discharge ICD-9 codes underestimated the true prevalence of obesity in an inpatient pediatrics population (Woo et al., 2009), while Kern et al. found that ICD-9-CM codes failed to identify the majority of veteran patients with comorbid chronic kidney disease (Kern et al., 2005). ICD-10 codes have also been shown to overestimate the prevalence of certain diagnoses, such as post-traumatic stress disorder (Rosner & Powell, 2009). However, recent evidence suggests that the introduction and use of ICD-10 coding may be associated with improved accuracy of co-morbidity coding for the majority of clinical conditions (Januel et al., 2011). It is unclear whether the improvement is due to the ICD-10 coding system itself or changes in coder and physician behavior.

Self-reported diagnoses from surveys or those that are mapped to ICD-9 or ICD-10 codes from surveys provide a much smaller number of chronic conditions for analysis, at a very coarse level of detail. Typically surveys do not include the breadth of chronic conditions a patient has or the specific types of chronic conditions (e.g., a specific type of cancer). For example, the HRS only allows researchers to investigate eight chronic conditions (hypertensions, diabetes, cancer, chronic lung disease, heart conditions, arthritis, stroke and psychiatric/emotional problems) and it does not allow them to drill down to what specific types of conditions a patient has (e.g., what type of cancer?). Thus, the use of surveys limits the ability to understand the true complexity of chronic disease combinations a patient is experiencing as well as the occurrence of less prevalent chronic conditions. In addition, self-reported diagnoses can be limited due to survey-related biases, such as recall, ascertainment and selection bias. For example, those individuals who avoid or who do not have access to healthcare may not be evaluated for potential chronic conditions of interest. Although evidence suggests that self-reported chronic conditions may be reasonably valid (Martin et al., 2000), self-reported diagnoses are not provider generated, may be subject to recall error by patients, and may not be captured in a sufficiently structured and systematic manner for analysis. Biases in self-reported diagnoses may be reduced through survey question structure; many surveys typically ask patients, “Has the doctor told you….?”. Overall, self-reported conditions can lead to non-uniform and inaccurate diagnosis categories and errors when mapping self-reported information to ICD-9 or ICD-10 codes.

In addition to the considerations described above, it is also important to note that validity of the presence of chronic conditions and reliability of reporting/detecting chronic conditions are two key issues that challenge MCC research. Researchers have attempted to improve validity by examining diagnoses across care settings and determining if patients have two or more claims reporting a specific diagnosis code over a given period of time to confirm disease occurrence. However, validity and reliability will remain a challenge given the vastness and complexity of many of the large databases and systems used to collect and analyze diagnostic information.

It is important to recognize that the trajectory of diagnosis coding in the United States is moving away from ICD-9 codes and towards larger, more detailed coding schemes, such as ICD-10 and SNOMED. In fact, on January 16^th, 2009 the Department of Health and Human Services published a final rule specifying an anticipated ICD-10 implementation date of October 1, 2013 (although this may be delayed). The World Health Organization (WHO) has already begun work on developing ICD-11. It is inevitable that diagnosis coding will continue to become more refined over time, providing researchers with the ability to study disease complexity at a level of detail not currently possible. Although “new” coding schemes will improve our ability to identify specific diagnoses of individuals with MCC, they will have some limitations.

The transition from ICD-9 to ICD-10, as well as to other future coding schema, will present challenges to researchers. During coding transition periods back-coding ICD-10 codes to ICD-9 and forward-coding ICD-9 codes to ICD-10 will be necessary for longitudinal analyses and comparative investigations. ICD-9 based indexes and measures, such as the Charlson Comorbidity Index and AHRQ’s Patient Safety Indicators, will also need to be translated to ICD-10 systems to support their continued use. There may be a “lag time” associated with re-specifying these tools, which researchers will need to be aware of. Additionally, there will most likely be a “testing” period after new coding systems are implemented, as researchers will need to explore the nuances and limitations of new systems prior to conducting analyses (Iezzoni, 2010). Researchers may also need to observe a data “black out” period as clinicians learn, perfect and then settle into new coding behaviors associated with the transition to ICD-10 (Januel et al., 2011). This “black out” period may also be needed by individual health systems and providers. The transition from ICD-9 to ICD-10 in the United States will not be smooth and universal. Health systems and providers will “go live” with ICD-10 at various points in time with different levels of success.

Despite the challenges, more refined coding systems will greatly enhance our ability to conduct research on less prevalent combinations of MCC. New coding systems will provide a very detailed level of diagnostic information.

Data Aggregation and Grouping Systems

Grouping systems, such as AHRQ’s clinical classification system and CMS’s Hierarchical Conditions Categories, are used to organize and aggregate diagnosis codes into different disease categories. These systems serve a variety of different purposes (e.g., research, risk-adjustment, etc.) and vary significantly in terms of which clinical conditions are considered and the number of diagnosis codes that are included in each disease group, as well as the number of groups (See ICD-9 Comparison Excel File). Regardless of their original intent or grouping methodology, however, many different types of grouping systems have been used to conduct MCC research, raising concerns about interpreting research results and comparing findings across MCC studies.

The decision to use specific grouping systems for MCC research should be informed by four key considerations: 1) the function, purpose and original intent of the grouper, 2) the behavior change that is desired by using the grouper to produce actionable information, 3) the end-users and their data needs ( e.g., data granularity), and 4) the research question. Researchers should not assume that a grouping system designed by and for one stakeholder group for one purpose is appropriate for another purpose. In fact, none of the currently available groupers are meant to serve multiple purposes (e.g., clinical decision support and risk-adjustment). Grouping systems are carefully designed and statistically calibrated to serve a specific aim. Using a grouping system for a different aim than intended can lead to meaningless results and misguided interpretation. MCC research which aggregates diagnosis codes should use grouping systems that are well documented, produce useful information for end-users (e.g., fine granularity for clinical decision support), and provide information that is meaningful, actionable and promotes provider behavior change (e.g., to reduce cost or improve care for specific groups). Grouping systems should be in alignment with the research questions at hand; research questions should ultimately drive MCC research designs (Wallace & Salive, 2013).

In choosing which grouping system to use for MCC research, stakeholder agendas matter. Each stakeholder group needs different types of information at varying levels of granularity. For example, those interested in clinical decision support needs a finer level of diagnostic information than risk-adjusters. Similarly, healthcare economists may need more detailed data than public health interventionists. Thus, it is important to consider the degree of coding granularity needed by each stakeholder. Understanding which stakeholder aims can be supported at specific levels of diagnostic granularity may be a beneficial area for investment for MCC researchers.

To determine which clinical classification systems exist and have been used for MCC or disease complexity research, a comprehensive grouping systems review was conducted. Grouping systems were identified through the literature review as well as input form the Co-Project Officers, TAG and key informants. Full descriptions of each classification system and the methodological issues to consider when using the grouper can be found in Appendix C. A condensed version of the results is shown in Exhibit 10 below.

Exhibit 10: Summary of Diagnostic Grouping Systems

We reviewed fourteen grouping systems which were found to serve a variety of different purposes ranging from risk adjustment to comparing morbidity across hospitals internationally. The grouping methodologies of the systems are remarkably different and vary in level of complexity. For example, diagnosis aggregation ranged from 25 categories for the Major Diagnostic Categories to 272 clinically-based groups with 1,080 subclasses for 3M’s Clinical Risk Groups. The difference has a dramatic consequence for the number of disease combinations that can be explored by researchers because the number of combinations (without replacement) scales as per the following formula: C(n,k)=n!/k!(n-k)! (Ammann 2011). In this formula “C” is the number of disease combinations, “n” is the number of disease groups in the grouping system, “k” is the number of disease groups included in the calculation, and “!” stands for factorial. Applying the formula to the Chronic Illness Disability Payment System (CDPS) for two-way disease combinations would result in the following calculation: C(n,K)=20!/(2!)*(18!); or 190 disease combinations could be studied. Using the same formula, but with three-way and four-way combinations, the CDPS model would provide 1,140 and 4,845 disease combinations respectively.

As shown in Exhibit 11 (logarithmic scale), the number of disease combinations for analysis increases rapidly as the number of chronic condition categories and number of diseases that are included in the combinations are increased. Thus, grouping systems with more chronic condition categories (greater “n”) will generate more chronic disease combinations (“C”) for analysis, especially when the number of diseases allowed in the disease combination calculation (“k”) is not truncated at an arbitrary level (i.e. calculate dyads or triads and then truncate at four or more diseases).

The number of diagnosis codes included in each grouping system could not be evaluated across all systems because the information is proprietary for privately owned grouping systems. The lack of transparency represents a methodological limitation and bias for researchers, as they cannot know which diagnoses were included in analyses and therefore assess the level of complexity captured by the grouping system. Despite their differences, the majority of groupers have been used in some form of multimorbidity research to-date. For example, Sorace and colleagues used the HCC model to study complexity in Medicare patients, while Salisbury and colleagues used John’s Hopkins ACG system to study general practice patients and Steinman and colleagues used the CCS to study VA patients (See Exhibit 5 in Section 6).When interpreting published MCC literature as well as designing future MCC research, the methodological differences between grouping systems should be reviewed and considered. For example, grouping systems that provide the finest level of diagnostic information and the greatest number of chronic condition categories, such as AHRQ’s CCS, would be most appropriate for research on less prevalent chronic disease combinations.

Exhibit 11: Possible Number of Chronic Disease Combinations by Diagnosis Grouping System

It is also important to note that many MCC researchers have designed and employ their own groupers or modify an existing grouper which affects the methodological quality of results. Decisions to include, exclude or aggregate diagnoses often are not reported in author’s methodology sections. Authors may state that the decisions were guided by physician consensus or technical expert panels, but do not list specific diagnosis codes that were included or excluded. The impact of grouping algorithms on other analysis steps and how they may affect the interpretation of results are also missing from studies. For example, authors do not discuss how costs are allocated to disease categories after eliminating certain diagnosis codes from analyses, nor the percentage and types of patients that are excluded from a study.

Consequently, researchers are creating unique diagnostic categories that may be fundamentally different from one another making it difficult to interpret how one researcher’s disease category for “cancer” compares to another. If researchers utilized publicly available, well documented grouping systems (standardization) such as AHRQ’s CCS, the challenges of interpreting results across studies would be minimized. However, it is not practical and may not make clinical sense to use only publicly available grouping systems. For example, some diagnosis codes may warrant exclusion from analyses because they are ambiguous (physician consensus does not yet exist on the diagnostic criteria for a particular condition) and over time grouping systems will become obsolete as new coding systems are adopted ( e.g., ICD-10) and new, more robust groupers are developed. Regardless of the future of grouping systems in MCC research, providing researchers and readers with the ability to understand how disease categories are constructed across studies will help make methodologies more transparent and results more interpretable.

Study Designs and Analytic Methods

As discussed above, most studies examine chronic conditions with the highest prevalence, costs, utilization, hospitalizations, and adverse events. For example, to study chronic disease prevalence in male Medicare patients, Black and colleagues limited their analyses to the “top ten” most prevalent diseases (Black et al., 2007). Other researchers have examined a somewhat larger number of conditions, but have purposely excluded less prevalent diseases (Schafer et al. 2010). It is critical to take the number of chronic conditions being investigated into account because prevalence estimates of multimorbidity are dependent on the number of diseases that are examined. This limitation was recently discussed by Salive, who found a prevalence estimate of 17.1% for 25–44 year old primary care patients when considering a list of seven conditions, and 73.9% when considering all possible conditions (Salive, 2013). Similarly, Fortin and colleagues found prevalence estimates of 47.3% among 45–64 year old primary care patients when considering seven conditions, and 93.1% when considering an open list (Fortin et al., 2010). Schneider and colleagues found that over 20% of Medicare beneficiaries had two or more chronic conditions when using the CMS Chronic Conditions Warehouse and a list of nine potential diseases, (Schneider et al., 2009). A considerably larger figure (52%) was reported for Veteran Affairs (VA) patients when almost triple the number of potential diseases (29 conditions) was considered (Yu et al., 2003). Thus, MCC prevalence can be under-estimated when fewer chronic conditions are investigated.

In addition to the number of chronic conditions that are studied, the specific types of chronic conditions that are examined across studies differ (e.g., cardiovascular conditions are studied vs. all possible chronic conditions). The “filtering” phenomenon can be observed when comparing a list of the chronic conditions that are investigated in two separate studies. For example, comparing the chronic conditions that were studied by Newcomer and colleagues (2011) (17 chronic conditions) to Chen and colleagues (2011) (8 chronic conditions), only three conditions were found to overlap. Although prevalence estimates for single conditions may be comparable across different data collection systems and surveys (Li et al., 2012), multimorbidity prevalence estimates across studies that include different conditions complicated the interpretation, generalizability and comparability of results.

MCC research has been conducted using a variety of different study designs (See Exhibit 12). However, the majority of MCC studies used retrospective cohort and cross-sectional designs, including secondary data analyses of data, due to the need for large sample sizes. It is important to note that these study designs have systematic limitations. For example, although retrospective cohorts are longitudinal and usually contain information on a large number of patients, they are often subject to attrition bias and bias due to changes in data collection procedures over time. This is an important concern for MCC studies, as prevalence estimates may be directly impacted by changes in data collection procedures, for example sampling strategies that change in terms of periodicity and population observed over time. Similarly, cross-sectional designs are not longitudinal and provide a “snap-shot” of information at one point in time. Future MCC research may benefit from employing longitudinal, prospective studies that provide researchers with large sample sizes, but also the ability to appropriately assess potential biases and study limitations as they occur. Preferred study designs for research on less prevalent combinations of MCC produce large sample sizes, are longitudinal, and provider researchers with the ability to assess the accuracy of diagnostic coding over time. Therefore, large prospective cohorts are advantageous for research on less prevalent combinations of MCC, although they are usually very expensive. The research questions that need to be answered may also dictate which study designs are most appropriate for certain MCC studies.

Exhibit 12: MCC Study Designs and Considerations

Author	Study Designs	Design Considerations
Ben-Noun 2001	Case-Control	Small sample size, prone to recall/retrospective and selection bias, suited for rare conditions.
Salisbury et al. 2011	Retrospective Cohort	Large sample size, prone to attrition bias, potential unknown coding practices and changes in data collection method, longitudinal.
Shelton et al. 2000	Prospective Cohort	Large sample size, prone to attrition bias, known methodology changes, potential for missing data, longitudinal, highly expensive.
Wolff et al. 2002	Cross-sectional	Large sample size, not longitudinal, cannot measure changes over time, cannot draw causal inferences, descriptive in nature.
Yu et al. 2003	Secondary Data Analysis	All type of sample sizes, potential unknown coding practices and data anomalies.

Other important considerations for MCC research are the limitations of the databases and algorithms used to house and analyze chronic conditions data. Over and underestimation of chronic disease prevalence may be due to database-specific characteristics. For example, the CMS Chronic Conditions Warehouse algorithm, which is used to estimate chronic disease prevalence, has been shown to underestimate the prevalence of chronic conditions requiring less frequent healthcare utilization, such as arthritis (Gorina & Kramarow, 2011). The underestimation is due to the fact that the reference period (or look back period) used in the CCW algorithm does not go back far enough to capture diagnoses that were reported on early healthcare claims and not on more recent claims. Setting (e.g., inpatient, nursing home, etc.) and other database characteristics also impact prevalence estimates and the interpretation of multimorbidity. For example, Schram and colleagues (2008) found that multimorbidity prevalence significantly varied across settings, from 22% in the inhospital setting to 82% in nursing homes. As expected, given the inherent differences between these populations, Fortin and colleagues (2010) found that MCC prevalence was much smaller in a general civilian population compared to family practice patients. In addition to the effect of “setting” on chronic disease prevalence estimates, Schram et al. (2008) also concluded that prevalence estimates are dependent on the number of chronic conditions being studied, the data collection method used to capture diagnosis information (i.e., ICD-9 vs. survey) and the time-frame being investigated, similar to the concerns raised by Gorina and Kramarow with the CCW’s look back period.

Database comprehensiveness, sampling frame and the patient population being studied all affect results. In drawing conclusions about analyses conducted on CCW data or AHRQ’s National Inpatient Sample (NIS) data, it is important to know that the CCW covers all Medicare patients, while the publically available version of the NIS covers only 20% of hospital discharges. Understanding these types of database characteristics will help researchers interpret the generalizability of their findings. The fact that the occurrence and clustering of MCC is time-dependent as patients grow older means that longitudinal datasets are best positioned to accumulate a patient’s chronic conditions over time and provide more accurate estimates of disease prevalence than cross-sectional assessments (France et al., 2011 & Wong et al., 2011). Time-dependency is an especially important concept for research on less prevalent combinations of MCC, as less common diseases are more likely to manifest over a long period of time, and diseases have different durations. Cross-sectional studies and analyses of longitudinal datasets covering limited time periods may not contain sufficient diagnostic information to study less prevalent combinations of MCC. Database size is important for research on less prevalent combinations of MCC. Large administrative datasets provide the best option due to the sheer volume of data and number of patients available for study. Less prevalent combinations of MCC are less likely to occur in small datasets with a limited number of patients and diagnoses to consider. Rare disease researchers face similar challenges.

Longitudinal databases have limitations. First, false discoveries and associations between chronic disease on the basis of too few observed diagnoses, inconsistent findings, and multiple test corrections need to be addressed (Wong et al. 2011). Additionally, the further back in time you examine longitudinal claims, the less accurately you can predict resource use and cost for a given condition or combination of conditions because of changing illness intensity over time. Although large administrative databases provide useful, current information on financial burden of disease (Riley, 2009), to more accurately predict resource use and cost, researchers need to know which diagnoses are “active” for patients currently receiving care. A laundry list of diagnoses is of little utility without a way to identify “active” conditions. Many patients will have ICD-9 codes on their past claims that represent errors, unconfirmed suspected diseases, and conditions that have been cured or are in remission. “Non-active” ICD-9 codes captured in longitudinal databases can negatively impact predictions of resource use and cost associated with MCC. Solutions may include an active problem list for patients and/or the use of supplemental data ( e.g., pharmacy and laboratory data) to confirm “active” diagnoses.

The challenges associated with conducting research on less prevalent MCC are very similar to those faced by researchers of rare diseases. Within the United States, a disease is considered to be rare when it affects less than 1 in 1000 individuals. Thus, like researchers studying less prevalent MCC, rare disease researchers are limited by small patient sample sizes and the inability of data sources to collect information on rare diagnoses, making it difficult to design clinical trials and test new treatments. In a research environment constrained by limited resources, rare disease research is given lower priority than conditions affecting more individuals (Griggs et al., 2009 & Ragni et al., 2012). It is important to consider that while any given rare disease by definition does not represent a prevalent illness, there are many rare diseases that may cumulatively affect a significant segment of the population. Finally, the likelihood of coding a rare chronic condition as a mistake may be similar to the likelihood of a patient truly having a rare disease and having this diagnosis coded accurately on a claim. Although not well studied, both research on rare diseases and research on less prevalent combinations of MCC may suffer from difficulty assessing validity.

Lastly, it is important to recognize that traditional statistical approaches may not be applicable to research on low-prevalence MCC. The issue of multiple comparisons is highly relevant for MCC research due to the number of chronic disease combinations that can be considered in the long tail. In fact, there are almost as many chronic disease combinations as there are patients. For example, if working at the three digit ICD-9 code level with approximately 1,000 diagnosis codes, about one-million pair wise comparisons would be possible. In this case, correcting for multiple comparisons using the Bonferroni method would require p-values of less than 0.00000005 to be significant. To understand the differences between low-prevalence MCC new or modified statistical approaches may need to be considered to address the multiple comparison limitation.

Reporting of MCC Research Methods

The amount and level of methodological detail published in MCC research papers varies greatly. Lack of consistency and detail regarding inclusion and aggregation of diagnosis codes hinders our ability to interpret research results and judge methodological quality. For example, in a manuscript describing chronic disease clustering, Schafer and colleagues provide a list of the specific ICD-10 codes they investigated in their study (Schafer et al., 2010). Conversely, in a paper looking at prevalence of chronic conditions in the VA Health Care System, Yu and colleagues did not report the ICD-9 codes that were examined. Instead the authors stated that “the diagnoses and specific codes used to identify each condition are available upon request from the authors” (Yu et al., 2003). For the purpose of developing this paper, we contracted Yu and his colleagues to obtain the list of the diagnoses and ICD-9 codes used in their study. Unfortunately, we were unable to reach the lead author and could not obtain the information.² However, an inquiry regarding a different, but related investigation (Yoon et al., 2011) resulted in a list of diagnoses and ICD-9 codes (in SAS) that could be examined and compared to other studies.

A lack of consistency and detail in reporting diagnosis codes is only one example of the variability in methods sections in published MCC studies. Variability is also a concern in understanding why specific conditions are examined vs. others, why certain diagnosis codes are excluded from analyses, how chronic condition categories are constructed, how costs are allocated to chronic condition categories after dropping certain diagnosis codes, etc. A repository of author’s ICD-9 codes is a potential mechanism by which authors could explain why certain diagnosis codes were included or excluded from specific analyses. However, to effectively address the variability across MCC studies a reporting framework or set of criteria, such as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), may be necessary to begin to standardize efforts and reporting across researchers (Moher et al., 2009).

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² Personal communication with available authors of Prevalence and Costs of Chronic Conditions in the VA Health Care System in Medicare Care Research and Review, 2003.

7. Data Systems and Datasets Review (Study Question #3)

What data systems and data sets exist that can be analyzed to better improve HHS’s understanding of and approaches to addressing numerous less prevalent combinations of chronic conditions? To answer the question we conducted a comprehensive review of data systems and datasets that were identified through the literature review, as well as input from the Co-Project Officers, TAG and key informants.

Overall, 17 data sources were reviewed and specific criteria were used to evaluate the appropriateness of each data source for use in less prevalent MCC research. The full data systems and datasets review is contained in Appendix B. A small set of excerpted data are shown in Exhibit 13.

Exhibit 13: Excerpt of Data Systems and Datasets Review

Data Type	Description	Less Prevalent MCC Research Considerations
Medicare Claims	CMS Chronic Conditions Warehouse, MedPAR, raw Medicare claims data. Nationally representative, but only for Medicare population. Large sample size. Longitudinal Diagnoses can be aggregated at various levels. Potentialconcerns for claims accuracy and sampling algorithms.	Appropriateness for Less Prevalent MCC Research: Strong Provides ability to study less prevalent MCC due to sample size, longitudinal design and diagnosis coding granularity.
HCUP Data	NIS, KID, and NEDS. Nationally representative, all-payer data source. Large sample size, NIS represents 20% of United States hospitals as specified. Larger versions of the NIS are also available that represent >90% of hospitals. Longitudinal. Diagnoses can be aggregated at various levels.	Appropriateness for Less Prevalent MCC Research: Strong Provides ability to study less prevalent MCC due to sample size, longitudinal design and diagnosis coding granularity. Not all states report the same number of diagnoses for each patient. Not all states capture unique patient identifiers; not all patients can be tracked across hospitalizations to identify all chronic conditions.
Medicaid Data	MAX Nationally representative, but only for Medicaid population. Longitudinal. Large sample size.	Appropriateness for Less Prevalent MCC Research: Strong Provides ability to study less prevalent MCC due to sample size, longitudinal design and diagnosis coding granularity.
Survey/ Questionnaire Data	NHANES, MEPS, BRFSS, NHIS, CAHPS, HRS, NHATS. Nationally representative, but contain unique limitations. Small sample size. Either cross-sectional or longitudinal. Limited number of diagnoses studied; limited granularity of data.	Appropriateness for Less Prevalent MCC Research: Weak Limited number of conditions investigated, reduced granularity, small sample size, often cross-sectional and focused on common conditions only
Other	VA, IHS, disease registries, state all-payer claims registries Non-nationally representative. Longitudinal.	Appropriateness for Less Prevalent MCC Research: Moderate Not appropriate for nationally-focused research

As discussed above, in general, research on less prevalent combinations of MCC can be most appropriately conducted using Medicare Claims, Medicaid Claims or HCUP data. These data sources are nationally-representative, longitudinal to capture the accumulation of diagnoses over time and contain a fine level of diagnostic codes. Other healthcare claims-based datasets such as state all-payer claims registries or Veteran Affairs data, are also good sources although they would not produce nationally-representative results and may be generalizable only to the specific populations included.

Survey or questionnaire data, while useful for certain types of MCC research, are limited because they include a small, select list of chronic conditions; typically not less prevalent conditions. Furthermore, diagnosis information from these data sources is often at a gross level of detail that inhibits the ability to study specific chronic conditions. For example, the Behavioral Risk Factor Surveillance System asks respondents about 15 conditions: myocardial infarction, coronary heart disease, skin cancer, other cancer, chronic obstructive pulmonary disease, depression, kidney disease, vision impairment, diabetes, and HIV/AIDS (CDC, 2011). Not only is the list not comprehensive, it also doesn’t capture information on the specific type of condition (i.e. what specific mental illness or cancer does the person have?). There is also the issue of respondents not specifying all of the chronic conditions they may have when interviewed or surveyed perhaps due to reluctance to divulge a specific condition. To ensure completeness, major national surveys were included in our review.

To enhance data richness and the ability to understand drivers of healthcare cost in addition to diagnostic information, researchers are able to link or match many of the datasets contained in our review. For example, Health and Retirement Study data can be linked with Medicare claims to better articulate the relationship between patient medical history, financial status, age, diagnoses and healthcare costs (ResDAC, 2013). Although data linking may improve data quality and robustness for specific variables, most linked datasets will not be advantageous for research on low-prevalence MCC due to small sample sizes and limited diagnostic information. However, these types of linked datasets may be an important source of information for future study on more prevalent chronic disease combinations. Linking claims to other Medicare data sources is one way to overcome limitations related to small sample sizes. For Medicare beneficiaries who are nursing home residents, linking Medicare claims data to the Minimum Data Set (MDS) assessment tool is possible. The MDS is part of the federally mandated assessment of all residents in Medicare or Medicaid certified nursing homes and contains items that measure physical, psychological and psychosocial functioning. Linking the MDS to claims data would permit in-depth analysis of how MCC patterns differ based on patient characteristics and also support analysis of the relationship between MCC and patient outcomes, at least for Medicare beneficiaries in nursing homes. Linking claims data to the Outcome and Information Assessment System (OASIS) would allow similar exploration for patients receiving home health services.

It is important to note that additional data sources may become available in the future that will be appropriate for research on less prevalent combinations of MCC. New data sources may include electronic healthcare record based registries, large employer databases, managed care patient registries, practice-based network data, and other data sharing and collection initiatives. Descriptions of these other potential data sources were not included in our review.

 

8. Opportunities and Considerations for Future Research (Study Question #4) and Conclusions

What combinations of less prevalent combinations of chronic comorbidities are most critical to address in terms of care utilization and cost? What are the future research considerations for MCC research?

While a number of studies in recent years have examined patients with MCC, patients with less common combinations have largely been overlooked. Given the growth and aging of the United States population, and the continual rise in healthcare costs, the “long tail” will likely only become larger and more complex and costly over time. Studying the population with less prevalent MCC combinations represents a shift from studying more prevalent chronic conditions to focusing on chronic disease complexity at a finer level of detail. Many combinations of MCC make up the long tail and, in the aggregate, a substantial number of patents with less prevalent MCC combinations and above-average costs and healthcare needs, are excluded from clinical research studies. Understanding how the long tail impacts healthcare costs and quality and improved treatment of MCC patients is a clear need.

Development of a research agenda for the population with low prevalence MCC should be guided by consideration of issues related to the data available for conducting this research and the types of research questions to be explored:

• Data for conducting research on this patient population: How well do existing data sources support research of this patient population? What types of additional types of data are needed? What types of additional studies are needed to understand the types of research on the long tail that existing data sources that can support?
• Research questions: What types of analyses are needed to improve our understanding of the long tail? What types of research are most likely to contribute to improvements in the effectiveness and efficiency of care for patients with MCC in the long tail? How can this research influence the way MCC patients are managed and treated, both in terms of patients with common combinations of chronic conditions and those with less prevalent combinations? What types of research studies can be informative for MCC patients?

As in all MCC research, different stakeholders will have different requirements in the level of clinical detail their disease models must support. Improved understanding of the MCC population has implications for quality of care, disease management, reimbursement, and the design of research studies. Below, we discuss potential topics for future research and initiatives on patients with low prevalence of MCC, organized by stakeholder.

Researcher & Interventionist Stakeholders

• Reproducing the long tail. To date, the long tail distribution of low-prevalence chronic disease combinations has been observed using Medicare claims data only. Other large, detailed sources of diagnostic information should be analyzed to determine if the long tail can be reproduced and if differences in distributions are evident among varying populations. Due to their large sample size and comprehensiveness, databases such as HCUP’s NIS, Medicaid’s MAX, and the National Ambulatory Care Survey (NAMCS) would be viable candidates for this type of research. Only recently has HCUP’s NIS and NAMCS been leveraged to study MCC prevalence and healthcare utilization (Ashman et al., 2013 & Steiner et al., 2013).
• Improving our understanding of how MCC prevalence and outcomes vary by patient characteristics. Because they have not been the focus of many prior studies, our understanding of patients with complex combinations of MCC who comprise the long tail is limited. Basic descriptive studies that examine the number of patients with various MCC combinations, the number of possible combinations, and the costs incurred by this population would be useful. Given the clinical detail (e.g., ICD-9 codes from claims data) needed to identify patients in the long tail, claims data (from Medicare, Medicaid, or private payers) have been the main data source for studies of the MCC population. Other potential data sources, such as surveys that collect information on self-reported conditions, typically lack the clinical detail needed to support research on the less prevalent MCC. While claims data have the large sample size and clinical detail that such studies require, they have several limitations that affect the types of MCC research that they can support:
  • Lack of demographic and socioeconomic variables. Medicare claims data can be linked to administrative data with information on enrollee characteristics, but the administrative data contains limited demographic information (e.g., gender, age, and race) and no real socioeconomic information.
  • Inclusion of patients only if treatment for a condition occurs in the specified time period. Only iif the patient is treated for the condition (i.e., has a claim with the ICD-9 code listed) during the period that the claims data cover will the diagnosis be included, and thus the data may underestimate prevalence. Some patients lack access to appropriate healthcare and claims data will not include all of their medical conditions. For other patients who have access, differences in screening, diagnosis, and coding practices can lead to differences in the types of diagnoses that are recorded in claims data.
  • Claims data are not representative of the United States population. For example, Medicare claims data are only available for Medicare fee-for-service beneficiaries; HCUP’s full NIS database represents about 90% of hospitals and 95% of discharges, but has unique limitations; and all-payer databases are only available for certain states.
  • Claims have limited information on patient outcomes. Alternatives or supplements to claims data will need to be explored to understand the relationship between MCC and patient characteristics and outcomes associated with MCC and the different treatment patterns for them. Linking claims to other data sets is one way that our understanding can be improved, at least for specific patient populations. For Medicare beneficiaries who are nursing home residents, linking Medicare claims data to the Minimum Data Set assessment tool would allow more detailed exploration of how MCC patterns differ based on patient characteristics and also support analysis of the relationship between MCC and patient outcomes. Linking claims data to the Outcome and Information Assessment System (OASIS) would allow similar exploration for patients receiving home health services. While only feasible for small numbers of patients, chart review for a sample of complex patients may be useful for better understanding and defining complexity. Given the unique disease combinations that one tends to find on the long tail, the generalizability of such results to other patients may be limited.
• Developing a reporting and theoretical framework. MCC researchers have utilized a variety of different systems of diagnostic classification and analytical methods. In the context of each individual research paper, these choices may have been reasonable and appropriate, but these choices can strongly influence the findings of research calculations. For example, an analysis with more diagnostic categories automatically finds more chronic disease combinations. Because findings depend on methods, it may be difficult or near impossible to combine research from diverse sources in order to synthesize consistent results. Different stakeholder groups are concerned with different aspects of MCC research; consequently, differences in diagnostic classification are likely to persist in future research. Standardization cannot be demanded merely for the sake of making literature review and synthesis easier. However, it can be suggested that authors of papers relevant to the MCC field begin considering how to cast their results in ways that facilitate comparison with the rest of the MCC literature, and that the scientific community address the development of a theoretical framework that would support more systematic reporting of MCC findings. In particular, methods developed for producing results that are invariant across methodologies, and for distinguishing clinically important combinations from those that are the inevitable result of arithmetic may be beneficial.
• Understanding how study conclusions are impacted by the classification system that is used. Little is known about how robust study findings are to the disease classification system that they use. As part of this study, we examined the ICD-9 codes used in three widely used classification systems: the CCS, HCCs, and the CCW. These systems vary with respect to the number of disease categories that they include—the CCS includes 285 categories, there are 70 HCC categories, and the CCW includes 27 chronic condition categories. These differences may contribute to differences in study findings that are purely driven by the classification system—a study that uses the CCS would presumably have more MCC combinations than one that uses the CCW just due to the difference in the number of categories in the two systems. The number of combinations actually observed in the data is an artifact of the classification plus the sample size.
  The classification systems also vary with respect to the number of ICD-9 codes that they use. The HCUP system includes virtually all of the 14,573 ICD-9 codes, the HCC system uses around 3,000 ICD-9 codes, while the CCW uses approximately 600 ICD codes. As a result, a higher proportion of patients would be classified into a disease category for studies that use the CCS than for studies that use HCCs or the CCW. Additional research is needed to understand the robustness of study findings to the classification system that is used.
• Cost patterns for those with MCC: Additional research on the healthcare costs incurred by patients in the long tail is important for understanding the potential savings from programs targeted at this population. There has been little research on the cost and utilization patterns for patients with specific combinations of MCC; the large number of possible combinations is a limiting factor. But identification of specific combinations associated with high costs is important for shaping development of cost effective programs for MCC treatment.
• Analysis of disease combinations (or clusters). For the most part, disease classification systems focus on individual conditions rather than specific combinations or clusters of conditions. As a result, few studies have examined the clustering of MCC, particularly for less prevalent MCC combinations for which there are a very large number of possible combinations. The lack of research on disease clusters is related to the large amounts of data that such studies require. Rare clusters cannot be identified without large amounts of data with detailed information on patient diagnoses (i.e., claims data). Analysis of such large data files will identify more disease combinations than it is possible to analyze. Additional research is needed to identify the disease clusters that should be the focus of future research efforts—for example, combinations associated with high-risk patient populations.
• Comparing MCC Studies Across Countries. MCC studies have primarily been conducted in the United States and Europe. Assessment of the data sources and methods used in these studies should be conducted to determine whether the results of these studies are comparable. That is, do data quality or infrastructure concerns suggest that research from one country may be more reliable than another? What do such comparisons suggest about how information and analytic techniques can be leveraged across international borders? Are there any potential implications for the treatment of MCC patients? Are there any studies of patients on the long tail that can be compared across countries or are there too few of these studies to draw any meaningful comparisons?
• Understanding the impact of transition to ICD-10. While this question will affect many types of research and transcends research on the long tail, the impact on MCC research resulting from efforts to map ICD-9 to ICD-10 is not known; at a minimum, this transition is likely to limit researchers’ ability to measure changes in disease prevalence and patient complexity over time. The ICD-10 transition will also affect classification systems such as HCUP and HCCs which are an important component of MCC research.

Patient and Provider Stakeholders

• Disease management programs. Clinical approaches often focus on individual diseases, without considering how the presence of MCC may affect healthcare needs. This is particularly true for patients in the long tail. As a result, clinicians have a very limited body of evidence-based knowledge for approaching the care for these patients. A focus of additional research should be improvements in disease management programs that are effective for patients with multiple conditions and prioritizes the role of care coordination. For example, how many different providers do MCC patients visit during the course of one year? Who do patients consider to be their “primary” physician? How many different physician offices and healthcare facilities do patients visit? How many different combinations of pharmaceutical drugs are MCC patients prescribed? What are the different types of systems indicators that can be used to monitor MCC patients?
• Patient perspectives on living in the long tail. There is a large patient stake in MCC research. For example, PatientsLikeMe expanded their list of potential diagnoses from 300 to 2,000 due to patient demand, a list that continues to increase. The “long tail” is not just a conceptual problem, but a problem that affects many patients. How do we bring the patient voice to MCC research? What would MCC patients like to know? How do we focus MCC efforts on patients and not a research paradigm or list of chronic conditions? One option is to provide opportunities through digital media for individuals with multiple chronic conditions to provide information about “a day in their lives” and their medical and health needs so that we can better understand what information is needed to better care for those with MCC. This would provide insights that cannot be obtained via data analyses, although it is not clear how generalizable findings would be to other MCC patients. Another option would be to develop patient-reported outcomes specific to MCC patients and to leverage patient-reported information that is collected through EHR systems. As EHRs continue to advance and online patient portals become more widely available, electronic information that is patient-derived may be a robust source of data that helps bring the patient voice to the forefront of MCC research.
• Understanding the different types of interactions between low-prevalence chronic disease combinations. When chronic diseases co-occur they can have additive, multiplicative or even protective effects. For example, body mass has been found to have a paradoxical effect on mortality in patients with rheumatoid arthritis (Escalante et al., 2005). Understanding the different types of interactions between chronic diseases can allow providers to better target groups of MCC patients for intervention (e.g., patients with chronic diseases that have a multiplicative effect).

Policymaker Stakeholders

• Payers. Reimbursement systems may fail to recognize the incremental costs associated with MCC, particularly for the less prevalent MCC combinations that comprise the long-tail. As a result, the full costs of caring for these patients may not be reflected in payment rates, potentially impacting quality and access to care for these patients. Additional research on patients with MCC combinations may lead to improvements in the ability of payment systems to recognize the incremental costs associated with specific MCC combinations, thus promoting appropriate reimbursement rates for these patients, promoting access to care. Some examples of potential research questions may include: How can patient diagnoses be more accurately identified and costs more accurately predicted? How can “active” diagnoses be determined compared to those patients are no longer seeking treatment for? What risk stratification levels may be warranted for persons with different combinations of chronic disease?
• Quality Measures and value-based purchasing programs. Quality measures may show skewed calculations due to inaccurately classified individuals if low-prevalence MCC are not accounted for. For example, a person with type 2 diabetes and Alzheimer’s disease may not be a good candidate for tight glycemic control. Exclusion of patients with specific MCC combinations is one option for dealing with this issue, but this would reduce the incentives to provide high quality care to this patient population, and also lead to a lack of relevant information on provider quality for MCC patients. Focusing on applicable quality measures that can be applied broadly across both MCC and non-MCC patients (e.g., related to patient-centeredness or care coordination, or self-management) is a better option. Development of MCC-disease-specific quality measures seems impractical for those on the long tail given the many MCC combinations and small sample sizes that would be available for measure calculation.
  Similarly, value-based purchasing programs may not account for disease complexity, as many metrics used in adjusting reimbursement are focused on single diseases and related clinical processes. The quality of care coordination and the ability to manage complexity may be more accurately assess by examining MCC patients, including those with low-prevalence conditions.

As is clear from the discussion above, there are many gaps in our knowledge of patients with less prevalent combinations of MCC. These gaps are partly a reflection of the data and analytic-related challenges that must be resolved to conduct research on this population and partly due to the inclination to focus on patients with individual conditions or on the more prevalent combinations of MCC. There are, however, a number of opportunities for future research that would improve our knowledge of the long-tail and perhaps lead to improvements in the care for this population. These potential research questions differ by stakeholder perspective. However, opportunities to share information, ideas and initiatives should be pursued across these perspectives to cultivate a community of professionals focused on improving care for all types of MCC patients.

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Appendices

The appendices listed below are supplemental materials and are attached to the white paper.

Appendix A - Literature Search Methodology

The literature search methodology outlines the MEDLINE search terms that were used to conduct the literature review of the peer-reviewed and grey literature related to prevalence of MCC, disease combinations, diagnosis coding, and databases and analytic techniques that have been used to conduct chronic disease research. The number of papers that were identified with each search term and combination are presented.

Appendix B – Review of National Datasets and Data Systems: Summary Tables

The review of national datasets provides a descripton of seventeen national data systems that can be used for multiple chronic conditions research, including a description of each data system, the diagnosis information measured in each data system, the cost, utilization, and clinical information captured in each data system, and the strengths, limitations, and appropriateness of each data system for MCC research.

Appendix C – Clinical Classification Systems ( Grouper ) Review

The Clinical Classification Systems (Grouper) Review provides a summary of fourteen systems for organizing and aggregating diagnosis codes into different disease categories, and an assessment of each grouper system’s feasibility for disease complexity research.

Appendix D - Technical Advisory Group List

The Technical Advisory Group (TAG) List provides of experts consulted about the overall conduct of the studies and their affiliations. TAG members participated in an initial in-person meeting in December 2012 and provided feedback on the original literature review to determine additional databases, grouping systems, and methods for studying MCC in disparities populations. TAG members then participated in a second meeting by teleconference in May 2013 to review and provide feedback on the first draft of the White Paper.

Appendix E - Key Informants

The list of key informants includes the individually interviewed experts and their affiliations. Key informants were identified by the ASPE Project Officers and the Technical Advisory Group (TAG). Key informant interviews were conducted to provide the Project Team with in-depth expertise on topics covered in the White Paper. Findings from the Key Informant Interviews have been incorporated throughout the White Paper.

Appendix A – Literature Search Methodology

The literature search methodology outlines the MEDLINE search strategy that was used to conduct the literature review of the peer-reviewed and grey literature related to prevalence of MCC, disease combinations, diagnosis coding, and databases and analytic techniques that have been used to conduct chronic disease research. The number of papers that were identified with each search term and combination are presented.

Search Strategy

MEDLINE

• Date – Last 10 Years (as of January 1, 2013)
• Language – English
• Limits – Human
• Limits – Abstract Available
• Search Field Tags – All fields

Key Terms

Search #	Key Terms	Number of Articles
#1	Chronic Disease/classification/epidemiology/economics	2425
#2	Multiple Chronic Conditions	127
#3	Multimorbidity	207
#4	Comorbidity	42895
#5	Disease Combinations	11
#6	Aging Chronic Disease	3236
#7	Health Expenditures	4888
#8	Economics	96447
#9	Healthcare Utilization	30769
#10	Healthcare Costs	27841
#11	Cost of Illness	11424
#12	United States	611178
#13	Clinical Coding	5252
#14	Medical Informatics	109606
#15	Multiple Chronic Conditions Data Sets	15
#16	# 1 AND #7	119
#17	# 1 AND #8	678
#18	# 1 AND #9	243
#19	# 1 AND #10	257
#20	# 1 AND #11	183
#21	#16 OR #17 OR #18 OR #19 OR #20	799
#22	# 21 AND #12	442
#23	# 4 AND #7	197
#24	# 4 AND #8	2611
#25	# 4 AND #9	1211
#26	# 4 AND #10	1032
#27	# 4 AND # 11	675
#28	# 22 OR #23 OR #24 OR #25 OR #26	3529
#29	#27 AND #12	1904
#31	# 6 AND #7	38
#32	# 6 AND #8	186
#33	# 6 AND #9	69
#34	# 6 AND #10	98
#35	# 6 AND #11	58
#36	#31 OR #32 OR #33 OR #34 OR #35	261
#37	# 13 AND #1	8
#38	# 13 AND #2	2
#39	# 13 AND #3	1
#40	# 13 AND #4	73
#50	# 13 AND #5	0
#51	# 37 OR # 38 OR #39 OR #40 OR #41	80
#52	# 14 AND #1	124
#53	# 14 AND #2	6
#54	# 14 AND #3	8
#55	# 14 AND #4	1217
#56	# 14 AND #5	2
#57	#52 OR #53 OR #54 OR #55 OR #56	1328
#58	#57 AND #12	545
#59	#2 OR #3 OR #5 OR #15 OR #22 OR #28 OR #36 OR #51 OR #58	3323

Article Selection

• A title review of 3,323 articles.
  • 3,201 articles eliminated due to one of following:
    • Single disease focus
    • Clinical interventions, therapies, and prevention practices
    • Quality improvement practices and interventions
    • Unrelated to topic
• An abstract review of 122 articles.
  • 53 articles eliminated due to one of the following:
    • Single disease focus
    • Clinical interventions, therapies, and prevention practices
    • Quality improvement practices and interventions
    • Unrelated to topic
• 69 relevant articles were identified during the abstract review for potential incorporation into the white paper. Additional relevant articles, not identified by the search methodology, were identified by the co-project officers, TAG and Key Informants.

Appendix B – Review of National Datasets and Data Systems: Summary Tables

The data systems review provides summaries of seventeen national datasets that can be used for multiple chronic conditions research, including a description of each data system, sponsor, the diagnosis information measured in each data system, the cost, utilization, and clinical information captured in each data system, and the strengths, limitations, and feasibility of each data system for MCC research.

Agency for Healthcare Research and Quality Datasets

Center for Disease Control and Prevention Datasets

Centers for Medicare & Medicaid Services Datasets

HMO Research Network Dataset

National Institute on Aging Dataset

Utah Department of Health Dataset

State of Colorado Dataset

University of Michigan Dataset

Appendix C – Clinical Classification Systems (Grouper) Review

The Clinical Classification Systems Review provides an overview of fourteen systems for organizing and aggregating diagnosis codes into different disease categories, and an assessment of each grouper system’s feasibility for disease complexity research.

Agency for Healthcare Research and Quality Grouper System

Axiomedics Research, Inc. Grouper System

Centers for Medicare & Medicaid Services Grouper Systems

Health Level Seven International Grouper System

Johns Hopkins University Grouper Systems

Thomson Medstat Medical Episode Grouper System

University of California, San Diego Grouper System

World Health Organization Grouper System

3M Health Information Systems Grouper Systems

Appendix D – Technical Advisory Group Members

The Technical Advisory Group (TAG) included experts from several federal HHS agencies who consulted about the content and design of the study. TAG members participated in an initial in-person meeting in December 2012 and provided feedback on the original literature review to determine additional databases, grouping systems, and methods for studying MCC in disparities populations. TAG members then participated in a second meeting by teleconference in May 2013 to review and provide feedback on the first draft of the White Paper.

 

Appendix E – Key Informants

Below is the list of key informants and their affiliations. Key informants were identified by the ASPE Project Officers and the Technical Advisory Group (TAG). Key informant interviews were conducted by telephone to provide the Project Team with in-depth expertise on topics covered in the White Paper. Findings from the Key Informant Interviews have been incorporated throughout the White Paper.