CHAPTER 5 Outcomes Research
The time when physicians chose treatment based solely on their personal notions of what was best is past. This era, although chronologically recent, is now conceptually distant. In a health care environment altered by abundant information on the Internet and continual oversight by managed care organizations, patients and insurers are now active participants in selecting treatment. Personal notions (“expert opinion”) are replaced by objective evidence. And the physician’s sense of what is best is being supplemented by patients’ perspectives on outcomes after treatment.
Outcomes research (clinical epidemiology) is the scientific study of treatment effectiveness. The word effectiveness is a critical one, because it pertains to the success of treatment in populations found in actual practice in the real world, as opposed to treatment success in the controlled populations of randomized clinical trials in academic settings (“efficacy”).1,2 Success of treatment can be measured using survival, costs, and physiologic measures, but frequently health-related quality of life (QOL) is a primary consideration.
Therefore, to gain scientific insight into these types of outcomes in the observational (nonrandomized) setting, outcomes researchers need to be fluent with methodologic techniques that are borrowed from a variety of disciplines, including epidemiology, biostatistics, economics, management science, and psychometrics. A full description of the techniques in clinical epidemiology3 is beyond the scope of this chapter. This chapter provides the basic concepts in effectiveness research and a sense of the breadth and capacity of outcomes research and clinical epidemiology.
In 1900, Dr. Ernest Codman proposed to study what he termed the “end results” of therapy at the Massachusetts General Hospital.4 He asked his fellow surgeons to report the success and failure of each operation and developed a classification scheme by which failures could be further detailed. Over the next 2 decades, his attempts to introduce systematic study of surgical end results were scorned by the medical establishment, and his prescient efforts to study surgical outcomes gradually faded.
Over the next 50 years, the medical community accepted the randomized clinical trial (RCT) as the dominant method for evaluating treatment.5 By the 1960s, the authority of the RCT was rarely questioned.6 However, a landmark 1973 publication by Wennberg and Gittelsohn spurred a sudden re-evaluation of the value of observational (nonrandomized) data. These authors documented significant geographic variation in rates of surgery.7 Tonsillectomy rates in 13 Vermont regions varied from 13 to 151 per 10,000 persons, even though there was no variation in the prevalence of tonsillitis. Even in cities with similar demographics and similar access to health care (Boston and New Haven, Conn.), rates of surgical procedures varied 10-fold. These findings raised the question of whether the higher rates of surgery represented better care or unnecessary surgery.
Researchers at the Rand Corporation sought to evaluate the appropriateness of surgical procedures. Supplementing relatively sparse data in the literature about treatment effectiveness with expert opinion conferences, these investigators argued that rates of inappropriate surgery were high.8 However, utilization rates did not correlate with rates of inappropriateness, and therefore did not explain all of the variation in surgical rates.9,10 To some, this suggested that the practice of medicine was anecdotal and inadequately scientific.11 In 1988, a seminal editorial by physicians from the Health Care Financing Administration argued that a fundamental change toward study of treatment effectiveness was necessary.12 These events subsequently led Congress to establish the Agency for Health Care Policy and Research in 1989 (since renamed the Agency for Healthcare Research and Quality, or AHRQ), which was charged with “systematically studying the relationships between health care and its outcomes.”
In the past decade, outcomes research and the AHRQ has become integral to understanding treatment effectiveness and establishing health policy. Randomized trials cannot be used to answer all clinical questions, and outcomes research techniques can be used to gain considerable insights from observational data (including data from large administrative databases). With current attention on evidence-based medicine and quality of care, a basic familiarity with outcomes research is more important than ever.
Key Terms and Concepts
The fundamentals of clinical epidemiology are best understood by thinking about an episode of treatment: a patient presents at baseline with an index condition, receives treatment for that condition, and then experiences a response to treatment. Assessment of baseline state, treatment, and outcomes are all subject to bias. We begin with a brief review of bias and confounding.
Bias and Confounding
Bias occurs when “compared components are not sufficiently similar.”3 The compared components may involve any aspect of the study. For example, selection bias exists if, in comparing surgical resection to chemoradiation, oncologists avoid treating patients with renal or liver failure. This makes the comparison unfair because, on average, the surgical cohort will accrue more ill patients. Treatment bias occurs when comparing, for example, standard stapedotomy with laser stapedotomy, but one procedure is performed by an experienced surgeon, and the other is performed by resident staff.
Similar to bias, confounding also has the potential to distort results. However, confounding refers to specific variables. Confounding occurs when a variable thought to cause an outcome is actually not responsible, because of the unseen effects of another variable. Consider the hypothetical (and obviously faulty) case in which an investigator postulates that nicotine-stained teeth cause laryngeal cancer. Despite a strong statistical association, this relationship is not causal, because another variable—cigarette smoking—is responsible. Cigarette smoking is confounding because it is associated with both the outcome (laryngeal cancer) and the supposed baseline state (stained teeth).
Assessment of Baseline
Most physicians are aware of the confounding influences of age, gender, ethnicity, and race. However, accurate baseline assessment also means that investigators should carefully define the disease under study, account for disease severity, and consider other important variables such as comorbidity.
Definition of Disease
It would seem obvious that the first step is to establish diagnostic criteria for the disease under study. Yet this is often incomplete. Inclusion criteria should include all relevant portions of the history, the physical examination, and laboratory and radiographic data. For example, the definition of chronic sinusitis may vary by pattern of disease (e.g., persistent vs. recurrent acute infections), duration of symptoms (3 months vs. 6 months), and diagnostic criteria for sinusitis (clinical examination vs. ultrasound vs. computed tomography vs. sinus taps and cultures). All of these aspects must be delineated to place studies into proper context.
In addition, advances in diagnostic technology may introduce a bias called stage migration.13 In cancer treatment, stage migration occurs when more sensitive technologies (such as CT scans in the past, and positron emission tomography scans now) may “migrate” patients with previously undetectable metastatic disease out of an early stage (improving the survival of that group), and place them into a stage with otherwise advanced disease (improving this group’s survival as well).14,15 The net effect is that there is improvement in stage-specific survival, but no change in overall survival.
The severity of disease strongly influences response to treatment. This reality is second nature for oncologists, who use tumor-node-metastasis stage to select treatment and interpret survival outcomes. It is intuitively clear that the more severe the disease, the more difficult it will be (on average) to restore function. Yet this concept has not been fully integrated into the study and practice of common otolaryngologic diseases such as sinusitis and hearing loss.
Recent progress has been made in sinusitis. Kennedy identified prognostic factors for successful outcomes in patients with sinusitis and has encouraged the development of staging systems.16 Several staging systems have been proposed, but most systems rely primarily on radiographic appearance.17–20 Clinical measures of disease severity (symptoms, findings) are not typically included. Although the Lund-Mackay staging system is reproducible,21 often radiographic staging systems have correlated poorly with clinical disease.22–26 As such, the Zinreich method was created as a modification of the Lund-Mackay system, adding assessment of osteomeatal obstruction.27 Alternatively, the Harvard staging system has been reproducible21 and may predict response to treatment.28 Scoring systems have also been developed for specific disorders such as acute fungal rhinosinusitis,29 and clinical scoring systems based on endoscopic evaluation have likewise been developed.30 The development and validation of reliable staging systems for other common disorders, as well as the integration of these systems into patient care, is a pressing challenge in otolaryngology.
Comorbidity refers to the presence of concomitant disease unrelated to the “index disease” (the disease under consideration), which may affect the diagnosis, treatment, and prognosis for the patient.31–33 Documentation of comorbidity is important, because the failure to identify comorbid conditions such as liver failure may result in inaccurately attributing poor outcomes to the index disease being studied.34 This baseline variable is most commonly considered in oncology, because most models of comorbidity have been developed to predict survival.32,35 The Adult Comorbidity Evaluation 27 (ACE-27) is a validated instrument for evaluating comorbidity in cancer patients and has shown the prognostic significance of comorbidity in a cancer population.36,37 Because of its impact on costs, utilization, and QOL, comorbidity should be incorporated in studies of nononcologic diseases as well.
Assessment of Treatment
Reliance on case series to report results of surgical treatment is time-honored. It is also inadequate for establishing cause and effect relationships. A recent evaluation of endoscopic sinus surgery reports revealed that only 4 of 35 studies used a control group.38 Without a control group, the investigator cannot establish that the observed effects of treatment were directly related to the treatment itself.3
It is also particularly crucial to recognize that the scientific rigor of the study varies with the suitability of the control group. The more fair the comparison, the more rigorous the results. Therefore a randomized cohort study in which subjects are randomly allocated to different treatments is more likely to be free of biased comparisons than observational cohort studies in which treatment decisions are made by an individual, a group of individuals, or a health care system. Within observational cohorts, there are also different levels of rigor. In a recent evaluation of critical pathways in head and neck cancer, a “positive” finding in comparison with a historical control group (a comparison group assembled in the past) was not significant when compared to a concurrent control group.39
Assessment of Outcomes
The distinction between efficacy and effectiveness, briefly discussed earlier, illustrates one of the fundamental differences between randomized trials and outcomes research. Efficacy refers to whether a health intervention, in a controlled environment, achieves better outcomes than does placebo. Two aspects of this definition need emphasis. First, efficacy is a comparison to placebo. As long as the intervention is better, it is efficacious. Second, controlled environments shelter patients and physicians from problems in actual clinical settings. For example, randomized efficacy trials of medications provide continuing reminders for patients to use their medications, and nonadherent patients are dropped from further study.
An efficacious treatment that retains its value under usual clinical circumstances is effective. Effective treatment must overcome a number of barriers not encountered in the typical trial setting. For example, disease severity and comorbidity may be worse in the community, in that healthy patients tend to be enrolled in (nononcologic) trials. Patient adherence to treatment may also be imperfect. Consider continuous positive airway pressure (CPAP) treatment for patients with obstructive sleep apnea. Although the CPAP is efficacious in the sleep laboratory, the positive pressure is ineffective if the patients do not wear the masks when they return home.40 A different challenge is present for surgical treatments, because community physicians learning a new procedure cannot be expected to perform it as effectively as the surgeon investigator who pioneered its development.
Fundamentals of Study Design
A variety of study designs are used to gain insight into treatment effectiveness. Each has advantages and disadvantages. The principal tradeoff is complexity versus rigor, because rigorous evidence demands greater effort. An understanding of the fundamental differences in study design can help interpret the quality of evidence, which has been formalized by the evidence-based medicine (EBM) movement. EBM is the “conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”41 EBM is discussed in detail elsewhere in this textbook. The following paragraphs summarize the major categories of study designs, with reference to the EBM hierarchy of levels of evidence (Table 5-1).41,42
Randomized clinical trials (RCTs) represent the highest level of evidence, because the controlled, experimental nature of the RCT allows the investigator to establish a causal relationship between treatment and subsequent outcome. The random distribution of patients also allows unbiased distribution of baseline variables and minimizes the influence of confounding. Although randomized trials have generally been used to address efficacy, modifications can facilitate insight into effectiveness as well. RCTs with well-defined inclusion criteria, double-blinded treatment and assessment, low losses to follow-up, and high statistical power are considered high-quality RCTs and represent level 1 evidence. Lower quality RCTs are rated level 2 evidence.
In observational studies, sometimes called cohort studies, patients are identified at baseline before treatment (or “exposure” in standard epidemiology cohort studies investigating risk factors for disease), similar to randomized trials. However, these studies accrue patients who receive routine clinical care. Inclusion criteria are substantially less stringent, and treatment is assigned by the provider in the course of clinical care. Maintenance of the cohort is also straightforward, because there is no need to keep patients and providers doubly blinded.
The challenge in cohort studies is to find an appropriate control group. Rigorous prospective and retrospective cohort studies with a suitable control group represent high-quality studies and can represent level 2 evidence. To obtain insight into comparisons of treatment effectiveness, these studies need to use sophisticated statistical and epidemiologic methods to overcome the biases discussed in the prior section. Even with these techniques, there is the risk that unmeasured confounding variables will distort the comparison of interest. Poor-quality cohorts without control groups, or inadequate adjustment for confounding variables, are considered level 4 evidence, because they are essentially equivalent to a case series.
Case-control studies are typically used by traditional epidemiologists to identify risk factors for the development of disease. In such cases, the disease becomes the “outcome.” In contrast to randomized and observational studies, which identify patients before exposure to a treatment (or a pathogen), and then follow patients forward in time to observe the outcome, case-control studies use the opposite temporal direction. This design is particularly valuable when prospective studies are not feasible, either because the disease is too rare or because the time interval between baseline and outcome is prohibitively long.
For example, a prospective study of an association between a proposed carcinogen (e.g., gastroesophageal reflux) and laryngeal cancer would require a tremendous number of patients and decades of observation. However, by identifying patients with and without laryngeal cancer, and comparing relative rates of carcinogen exposure, a case-control study can obtain a relatively quick answer.43 Because the temporal relationship between exposure and outcome is not directly observed, no causal judgments are possible, however. These studies are considered level 3 evidence.
Case Series and Expert Opinion
Case series are the least sophisticated format. As discussed earlier, no conclusions about causal relationships between treatment and outcome can be made because of uncontrolled bias and the absence of any control group. These studies are considered level 4 evidence. If case studies are unavailable, then expert opinion is used to provide level 5 evidence.
Other Study Designs
There are numerous other important study designs in outcomes research, but a detailed discussion of these techniques is beyond the scope of this chapter. The most common approaches include decision analyses,44,45 cost-identification and cost-effectiveness studies,46–48 secondary analyses of administrative databases,49–51 and meta-analyses.52,53 Critiques of these techniques are referenced for completeness.
Grading of Evidence-Based Medicine Recommendations
EBM uses the levels of evidence described earlier to grade treatment recommendations (Table 5-2).54 The presence of high-quality RCTs allows treatment recommendations for a particular intervention to be ranked as grade A. If no RCTs are available, but there is level 2 or 3 evidence (observational study with a control group or a case-control study), then the treatment recommendations are ranked as grade B. The presence of only a case series would result in a grade C recommendation. If only expert opinion is available, then the recommendation for the index treatment is considered grade D.
|Grade of Recommendation||Level of Evidence|
|B||2 or 3|
Measurement of Clinical Outcomes
Clinical studies have traditionally used outcomes such as mortality and morbidity, or other “hard” laboratory or physiologic endpoints,55 such as blood pressure, white cell counts, or radiographs. This practice has persisted despite evidence that interobserver variability of accepted “hard” outcomes such as chest x-ray findings and histologic reports are distressingly high.56 In addition, clinicians rely on “soft” data, such as pain relief or symptomatic improvement to determine whether patients are responding to treatment. But because it has been difficult to quantify these variables, these outcomes have until recently been largely ignored.
An important contribution of outcomes research has been the development of questionnaires to quantify these “soft” constructs, such as symptoms, satisfaction, and QOL. Under the Classical Test Theory, a rigorous psychometric validation process is typically followed to create these questionnaires (more often termed scales, or instruments). These scales can then be administered to patients to produce a numeric score. The validation process is introduced herein; a more complete description can be found elsewhere.57–59 The three major steps in the process are the establishment of reliability, validity, and responsiveness; in addition, increasing consideration is also given to burden.
More recently, item response theory (IRT) has been used to create and evaluate self-reported instruments. A full discussion of IRT is beyond the scope of this chapter. In brief, Item Response Theory uses mathematic models to draw conclusions based on the relationships between patient characteristics (latent traits) and patient responses to items on a questionnaire. A critical limitation is that IRT assumes that only one domain is measured by the scale. This may not fit assumptions for multidimensional QOL scales. However, if this assumption is valid, IRT-tested scales have several advantages. IRT allows for the contribution of each test item to be considered individually, thereby allowing the selection of a few test items that most precisely measure a continuum of a characteristic. In other words, because each test item is scaled to a different portion of the characteristic being tested, the number of questions can be reduced.65–68 Therefore, IRT lends itself easily to adaptive computerized testing, allowing for significantly diminished testing time and reduced test burden.65 In the future, IRT will likely be the basis to more and more new questionnaires evaluating outcomes, including QOL.
Categories of Outcomes
In informal use, the terms health status, function, and quality of life are frequently used interchangeably. However, these terms have important distinctions in the health services literature. Health status describes an individual’s physical, emotional, and social capabilities and limitations, and function refers to how well an individual is able to perform important roles, tasks, or activities.58 QOL differs because the central focus is on the value that individuals place on their health status and function.58