Clinical phenotyping is currently used to guide pharmacological treatment decisions in chronic obstructive pulmonary disease (COPD), a personalized approach to care. Precision medicine integrates biological (endotype) and clinical (phenotype) information for a more individualized approach to pharmacotherapy, to maximize the benefit versus risk ratio. Biomarkers can be used to identify endotypes. To evolve toward precision medicine in COPD, the most appropriate biomarkers and clinical characteristics that reliably predict treatment responses need to be identified. FEV1 is a marker of COPD severity and has historically been used to guide pharmacotherapy choices. However, we now understand that the trajectory of FEV1 change, as an indicator of disease activity, is more important than a single FEV1 measurement. There is a need to develop biomarkers of disease activity to enable a more targeted and individualized approach to pharmacotherapy. Recent clinical trials testing commonly used COPD treatments have provided new information that is likely to influence pharmacological treatment decisions both at initial presentation and at follow up. In this Perspective, we consider the impact of recent clinical trials on current COPD treatment recommendations. We also focus on the movement toward precision medicine and propose how this field needs to evolve in terms of using clinical characteristics and biomarkers to identify the most appropriate patients for a given pharmacological treatment.
Chronic obstructive pulmonary disease (COPD) is a complex condition, encompassing many elements that contribute to its clinical presentation. COPD is also heterogeneous, as these different elements vary in both presence and severity between patients (1). These characteristics may be dynamic, varying over time within the same patient (2). The variability between patients with COPD means that an individualized approach is required for pharmacological treatment (2, 3).
Clinical phenotypes are subgroups of patients defined by clinical characteristics and sharing common clinical outcomes (e.g., exacerbations, response to treatment) (4). In 2011, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposed a combined assessment of FEV1, symptoms, and exacerbation history, resulting in four groups representing clinical phenotypes (A/B/C/D) (5). Pharmacological treatments were proposed for each phenotype, targeting the short- and long-term relief of symptoms and the long-term risk reduction of future events such as exacerbations (or death). Potential criticisms of this approach are that these clinical phenotypes require prospective validation regarding their links with future outcomes and treatment responses and that some pharmacological treatment propositions were not supported by firm clinical evidence (3). Nevertheless, many national respiratory societies have embraced the GOLD principles to construct COPD guidelines, although with several variations (6).
Each clinical feature of COPD is likely caused by more than one biological mechanism. Consequently, pharmacological targeting of clinical characteristics does not specifically match the drug to underlying biological mechanisms and may result in limited efficacy. An endotype is a subtype of a (clinical) condition defined by a distinct pathophysiological mechanism (3). An endotype gives rise to one or more clinical characteristics, and clinical phenotypes can be the result of multiple endotypes. The “precision medicine” strategy uses both biological (endotype) and clinical (phenotype) information to identify the most appropriate individuals for a given pharmacological treatment, to maximize the benefit-versus-risk ratio (7). COPD pharmacotherapy faces a challenge to incorporate precision medicine, as easily accessible biomarkers that identify clinically relevant endotypes need to be developed.
Recent studies have raised issues about the clinical characteristics and biomarkers that can reliably predict treatment responses and whether the existing evidence supports current pharmacological treatment recommendations. This article focuses on current controversies in COPD pharmacological management and considers the future evolution of COPD pharmacotherapy toward precision medicine.
At a population level, there is a loose association in COPD cross-sectional studies between FEV1 and symptoms; consequently, FEV1 poorly predicts the symptom burden on an individual level (1) and is a suboptimal measurement to guide symptom-based treatment decisions. However, the change in FEV1 in COPD randomized clinical trials (RCTs) is still a useful measurement, as improvements in FEV1 associate with improvements in symptoms, health status, and exacerbation rates (8, 9).
Inhaled corticosteroid/long-acting β-agonist (ICS/LABA) combinations reduce exacerbation rates and improve lung function and health status (10–13). RCTs of ICS/LABA combinations commonly enrich the population to include individuals more likely to exacerbate, to maximize treatment efficacy (12–14). The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and COPDgene longitudinal cohort studies demonstrated that the past exacerbation history is a better predictor of future exacerbations than FEV1 (15, 16). Furthermore, a notable proportion (22%) of patients with FEV1 50 to 80% predicted in ECLIPSE had two or more exacerbations (defined as frequent exacerbators) each year for 3 years (15). Therefore, relying on FEV1 to identify patients at risk of exacerbations (e.g., using 50% predicted as a threshold) may prevent some patients from receiving appropriate pharmacotherapy. Indeed, recent evidence shows that ICS/LABA combinations reduce exacerbations in patients with an exacerbation history and FEV1 up to 70% predicted (14).
Long-acting bronchodilators improve lung function, thereby improving symptoms and exercise performance, and prevent exacerbations (11, 17, 18). These agents show similar efficacy in patients with moderate (GOLD II) compared with more severe (GOLD III/IV) COPD (19, 20), indicating that FEV1 does not predict bronchodilator treatment response. Furthermore, short-acting bronchodilator reversibility does not predict response to long-acting bronchodilators or ICS/LABA combinations (21, 22), as bronchodilator reversibility can change between visits (23), and patients with a negative reversibility test can still obtain clinical benefit from a long-acting bronchodilator.
An “FEV1-free” approach to pharmacotherapy in COPD has been proposed (24), where the use of long-acting bronchodilators would be directed by symptoms and the presence of exacerbations. The use of antiinflammatory treatments would be recommended if the patient continues to suffer exacerbations despite appropriate bronchodilator treatment (Figure 1). The current GOLD C and D categories comprise three different patient subgroups: low FEV1 alone, exacerbation history alone, or both. This causes confusion in clinical practice regarding pharmacological treatments. The FEV1-free approach makes the definition of GOLD C and D more homogeneous, including only frequent exacerbators. The FEV1-free approach applies to pharmacotherapy only, as spirometry is required for COPD diagnosis, and FEV1 remains a prognostic risk marker for mortality (25) and is required when considering interventional care for COPD (i.e., lung volume reduction or lung transplantation).
The different components of COPD can be categorized into severity, activity, and impact groupings (26). Severity refers to functional impairment, including airflow limitation, hyperinflation, arterial hypoxemia, and reduced exercise capacity (27). Disease activity refers to features associated with disease progression, such as exacerbations, FEV1 decline, and weight loss (26). Impact refers to the individual patient’s perception of disease severity and activity (26). Bronchodilators improve severity (lung function), which consequently reduces the impact level. However, as already discussed, the level of impact rather than severity should guide individual treatment decisions regarding bronchodilator use; this is illustrated in Figure 2, which also shows that pharmacological treatments can target disease activity, such as preventing exacerbations. RCTs have used inclusion criteria to select individuals with more active disease on the basis of exacerbation history (13, 14, 28, 29). We now consider alternative means of assessing disease activity, through longitudinal assessments and biomarkers.
The speed of lung function loss with age is the paradigmatic marker of disease activity. However, years of follow up are needed to be confident of the rate of change. FEV1 does not decline precipitously in all treated patients with COPD, remaining stable or even improving in a significant proportion (30). Furthermore, a recent analysis of three independent cohorts showed that COPD can be the result of different trajectories of lung function decline, depending on underlying mechanisms, including failure to reach maximal lung growth (31). The mean rate of lung function decline was 27 ml/yr compared with 53 ml/yr in individuals with low and normal FEV1 in early adult life, respectively, suggesting greater disease activity in the latter group. A single FEV1 measurement is a severity marker but may be misleading regarding disease activity.
COPD RCTs have not proved, as a primary endpoint, that pharmacotherapy reduces the rate of lung function decline. However, post hoc analysis of a 3-year RCT showed a reduced rate of FEV1 decline with ICS/LABA treatment and the monocomponents (32), whereas a prespecified subgroup analysis showed similar results for long-acting muscarinic antagonist (LAMA) treatment in GOLD II patients (19). The SUMMIT (Study to Understand Mortality and Morbidity in COPD) study showed that ICS/LABA treatment, but not LABA monotherapy, reduced the rate of FEV1 decline in patients with COPD with FEV1 50 to 70% predicted, but a definitive conclusion from this secondary outcome could not be made, as the primary outcome (mortality) was negative, and a hierarchical testing approach was used (33). These studies have shown attenuation of FEV1 decline by pharmacotherapies ranging from 6 to 16 ml/yr. These effect sizes may be greater in patient subgroups with more rapid FEV1 decline; risk factors for rapid decline include current smoking, exacerbations, and emphysema (15, 34). Smoking cessation reduces the rate of lung function decline (35), and the evidence reviewed here suggests an effect of long-acting bronchodilators and ICS through exacerbation prevention, thereby reducing disease activity. There is a need for RCTs that specifically address pharmacological approaches to prevent emphysema progression.
Fibrinogen is a biomarker of cardiovascular risk and predicts exacerbation risk and mortality in patients with COPD (36). Plasma fibrinogen measurements have been accepted by the U.S. Food and Drug Administration as a biomarker for enriching RCTs with patients more likely to suffer with these outcomes, when used in conjunction with clinical information such as the past history of exacerbations. Importantly, fibrinogen cannot yet be used at an individual level in clinical practice; it is a biomarker that can be used at a group level to identify patients with greater disease activity. There are currently no disease activity biomarkers validated for use at an individual level.
Biomarkers that have been investigated include club cell protein 16 (CC16) and soluble, circulating form of the receptor for advanced glycation end products (sRAGE). CC16 is a protective immunosuppressant secreted by club cells; low CC16 levels are associated with lung function decline (37, 38). sRAGE may be associated with emphysema severity and progression (39). Most of the evidence for these biomarkers comes from cohort studies or small clinical trials. Their potential usefulness to enrich the population studied, and/or to measure treatment effects, should be prospectively evaluated in large RCTs. The validation and harmonization of the laboratory measurement methods also needs to be established.
A panel of several biomarkers may provide more reliable information than a single one; for example, patients with persistent systemic inflammation assessed by blood leukocytes and serum IL-6, C-reactive protein, and fibrinogen had significantly higher all-cause mortality (13 vs. 2%) and exacerbation frequency (1.5 vs. 0.9/yr) (40). In addition, a biomarker panel increased the ability of clinical variables to predict future exacerbations and mortality (41, 42). Biomarkers of disease activity are likely to be most useful when used with clinical measurements.
Combination inhalers containing a LABA and LAMA cause improvements in FEV1 compared with placebo that are usually approximately 250 to 300 ml at peak and 150 to 200 ml at trough (43–45). These combination inhaler effects on FEV1 are greater than long-acting bronchodilator monotherapies, with treatment differences of approximately 150 ml at peak and 50 to 90 ml at trough (43–45). The important clinical question is the degree of symptom improvement associated with these lung function changes. Initial studies used lung function as a primary endpoint for regulatory purposes and were not specifically powered or designed for patient-reported outcome (PRO) measurements (44–46). These studies showed that the mean PRO improvements with LABA/LAMA combinations versus placebo exceeded the minimal clinically important difference (MCID) thresholds for breathlessness scores (>1-point change in the transition dyspnea index focal score) and health-related quality of life (>4-point reduction in the St. George’s Respiratory Questionnaire total score) (47), whereas monotherapies often failed to meet these MCID thresholds versus placebo. Individual responder analysis also showed that significantly more patients reached the MCID thresholds with dual therapy versus monotherapy. However, the mean differences between dual bronchodilators versus monotherapy were often small in magnitude or not statistically significant. Subsequent studies specifically designed with PROs as the primary endpoint (48, 49), and pooled analysis with greater statistical power (50), have shown statistically significant differences of 0.5 for transition dyspnea index and 2 for St. George’s Respiratory Questionnaire for this treatment comparison. These are lower than the MCID thresholds, but the associated reductions in reliever medication use suggest clinical relevance (43, 47).
The daily variation in lung function is reduced with two short-acting bronchodilators compared with one, suggesting greater stabilization of airway tone (23). LABA/LAMA combinations may also provide increased airway stabilization. RCTs usually focus on improvements in FEV1 and symptoms with bronchodilators, but the prevention of short-term clinical deterioration, which may progress to exacerbation, is also of importance.
Long-acting bronchodilator monotherapies reduce exacerbation rates (11, 18). There is also a greater effect on exacerbations with LABA/LAMAs compared with LAMA monotherapy in patients at risk of exacerbations; indacaterol/glycopyrronium reduced exacerbations requiring oral corticosteroids and/or antibiotics by 12% compared with glycopyrronium (29). There was also a reduction in mild exacerbations requiring increased bronchodilator treatment, which may be due to better airway stabilization with LABA/LAMA treatment.
Exacerbations may be associated with increased airway inflammation (51), but there is no consistent evidence from clinical trials that bronchodilators have antiinflammatory effects. Long-acting bronchodilators improve airflow obstruction, air trapping, and hyperinflation, thus reducing dyspnea and improving exercise performance (17). These improvements in lung mechanics and clinical status probably allow patients to cope better with the pathophysiological impact of factors that may trigger exacerbations, such as infections (52).
Patients with COPD at high risk of cardiovascular events are often excluded from RCTs. The SUMMIT study in patients at increased risk of cardiovascular disease showed no increase in adverse cardiac events with LABA treatment (33). More studies in high-risk patients with COPD, and real-world observational studies, would provide further reassurance about long-acting bronchodilator safety.
Many RCTs have shown a reduction in exacerbations of approximately 25 to 30% for various ICS/LABAs versus LABAs, suggesting a “class effect” for ICSs (12–14). ICSs may have side effects; RCTs, metaanalyses, and observational studies concur in finding an increased rate of nonfatal pneumonia in patients receiving ICSs (11, 13, 14, 53). Risk factors include past exacerbations, low body mass index, or low FEV1 (54); this may explain the lack of increase in pneumonia events in the SUMMIT study, which enrolled patients with moderate COPD, without a requirement for past exacerbations. This effect may relate more to the dose than to the properties of individual molecules. Observational studies suggest increased risk of mycobacterial infection (55, 56), diabetes occurrence or aggravation (57), bone fractures (58), and cataract (59) with ICSs, but residual confounders could influence the results. RCT evidence exists only for skin bruises (60) and loss of bone mineral density (58), indicating that ICSs can cause clinically relevant systemic effects. Other ICS systemic side effects are difficult to firmly demonstrate in RCTs due to the long duration of follow up and large sample size required.
Patients with COPD with greater sputum eosinophil counts have a better response to corticosteroid treatment (61, 62). Sputum sampling is only performed in specialist centers. Blood eosinophil counts are more accessible and show a degree of correlation to sputum eosinophils (63). Post hoc analyses of RCTs investigating ICS/LABA combinations versus LABA monotherapy have reported greater effects of ICS/LABA on exacerbation prevention in patients with higher blood eosinophil counts (64–66). Post hoc analysis of the INSPIRE (Investigating New Standards for Prophylaxis in Reduction of Exacerbations) study reported that an ICS/LABA had a significantly greater effect on exacerbations than a LAMA in patients with blood eosinophils greater than 2% (rate ratio, 0.75), but there was no difference with blood eosinophils less than 2% (65). Similarly, ICS withdrawal in the WISDOM (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) study increased the exacerbation rate only in patients with blood eosinophils greater than 2% (67). Although a threshold of 2% has been commonly used in these analyses, the effects of ICS appear to become greater when using higher thresholds (64, 66, 67), and it is not clear whether percentage or absolute eosinophil counts should be used. It has also been reported that blood eosinophils greater than 2% predict a reduced rate of FEV1 decline with ICSs compared with placebo (difference, 33.9 ml/yr) (68). Prospective RCTs are needed to validate the use of blood eosinophil counts to predict ICS response and to identify the appropriate cut-off level. The mechanism(s) for the differential effects of ICSs according to eosinophil counts remain unclear. Higher blood eosinophil counts in some (but not all) analyses predict higher exacerbation rates (63, 69), suggesting more active disease, with eosinophils greater than or equal to 340 cells/μl predicting an increased exacerbation risk in patients with COPD in the Copenhagen general population study (69).
GOLD makes propositions for initial pharmacotherapy, with different options for groups A through D (5). Pharmacotherapy for groups A and B is dominated by short- and long-acting bronchodilator treatments. The majority of patients with COPD on long-acting bronchodilator monotherapy remain significantly breathless (70). There is no evidence to suggest which patients should initially receive an LABA/LAMA combination. This could be investigated in patients who have not received long-acting bronchodilator treatments previously, unlike the majority of patients in published studies. ICS/LABAs should not be used for groups A and B, and RCTs have shown superiority for LABA/LAMAs over ICS/LABAs in these patients for lung function and symptoms (71, 72).
Groups C and D include patients with frequent exacerbations defined by a history of two or more moderate to severe exacerbations or one hospitalization in the last year. Clinical outcomes, including future exacerbation risk, health-related quality of life, FEV1 decline, and mortality are significantly impaired in patients with two or more exacerbations per year (15). Many exacerbation events are unreported (73, 74), and a threshold of two events using patient recall may underestimate the true event rate. Exacerbation frequency may change (15), and using a lower threshold (a single exacerbation event in a year) may identify patients with no further events. GOLD uses one hospitalization to define a patient at high risk of future exacerbations, recognizing the importance of event severity, which influences the time to recovery (75). RCTs assessing the effects of drugs on exacerbation rates have historically used one exacerbation in the previous year as an inclusion criterion (13, 14). Current GOLD propositions assume that results from these studies predict the effects in patients with two or more exacerbations per year, but this mostly remains untested.
The positioning of LAMAs as a first-line option for frequent exacerbators is based on robust evidence demonstrating effects on exacerbations compared with placebo (18, 76). Furthermore, the INSPIRE study in patients with severe airflow obstruction and a history of exacerbations showed no difference in exacerbation rate after 2 years of treatment with tiotropium compared with fluticasone propionate/salmeterol (77). Systemic corticosteroid treatment for exacerbations was less frequent with ICS/LABA treatment, and antibiotic use was less frequent with tiotropium. This suggests that initial pharmacotherapy could be tailored to prevent exacerbation subtypes.
GOLD does not provide guidance on pharmacological strategies during follow up, when treatment may be adjusted according to the initial treatment response; this potentially includes stopping ineffective therapies. The comparative benefits of adding or switching therapies if patients remain symptomatic on initial therapy need to be better characterized.
The introduction of dual bronchodilator combinations raises the issue of the comparative efficacy of LABA/LAMAs versus ICS/LABAs. Indacaterol/glycopyrronium had a greater effect on exacerbations than salmeterol/fluticasone propionate in a subgroup of patients with one exacerbation in the previous year included in an RCT (78). The recently published FLAME (Fluoxetine for Motor Recovery after Acute Ischaemic Stroke) study recruited 3,362 patients with one or more exacerbations in the previous year to compare these combinations over 1 year (28). Indacaterol/glycopyrronium showed superiority on the rate of all exacerbations (11% reduction, P = 0.003), with moderate to severe exacerbations reduced by 17% (P < 0.001). There was evidence of significantly better FEV1 (62 ml) and health status and lower pneumonia incidence with indacaterol/glycopyrronium. Although INSPIRE showed similarity between LAMAs and ICS/LABAs for exacerbation reduction (77), FLAME now demonstrates a superiority for LABA/LAMAs in this regard, across different severities of exacerbation. ICS treatment has been perceived to be an essential part of exacerbation prevention strategies; FLAME shows an effective alternative strategy without ICS.
There is little evidence for exacerbation reduction when stepping up from two medications (either ICS/LABA or LAMA/LABA) to triple therapy (79), although there are benefits for lung function and patient-reported outcomes (80, 81). An RCT comparing ICS/LABA to LABA allowed concomitant tiotropium use; a subgroup analysis showed a 28% reduction in exacerbations comparing triple therapy to LABA plus LAMA (13). RCTs with triple therapy in a single inhaler are ongoing and will provide relevant data.
The phosphodiesterase 4 inhibitor roflumilast has broad antiinflammatory effects on different cell types (82). Roflumilast reduces exacerbation rates in patients with COPD with chronic bronchitis, severe airflow obstruction, and a previous history of exacerbations (83, 84). This precision medicine approach (3) targets a subgroup most likely to benefit. The biological rationale for this differential effect remains unclear, and the nature of this effect is under evaluation (85). Roflumilast improves FEV1 by approximately 50 to 80 ml in patients with COPD (86, 87) but without consistent benefits on symptoms (84, 87). Roflumilast can cause nausea, reduced appetite, gastrointestinal disturbance, and weight loss, so it is usually prescribed after better-tolerated inhaled treatments. A recent RCT confirmed that roflumilast decreased exacerbations in patients with COPD with chronic bronchitis on multiple inhaled medications (87), and in real life roflumilast may decrease readmission rates in patients hospitalized for COPD (88). Further work is needed to improve our understanding of the narrowly defined patient populations where the clinical benefit of roflumilast is greatest, and attempts at altering the dosage regimen to minimize side effects are ongoing (89).
Macrolides have immunomodulatory and antibacterial effects (90, 91). Two systematic reviews of COPD RCTs confirmed a significant reduction in exacerbation rates with macrolide therapy (92, 93). The most compelling data are for azithromycin therapy (94, 95), although the optimal dosage is unclear, as daily and three times weekly dosing both demonstrate efficacy (90). The patient population most likely to benefit has not been identified (93). A post hoc analysis of the largest trial suggests an increased likelihood of benefit in older patients with milder disease and ex-smokers (96). The potential risks include hearing loss (94) and prolonged QTc interval, raising concerns about cardiovascular safety (97). Population-based studies have provided contradictory evidence regarding cardiovascular safety (98, 99). Some have suggested that chronic macrolide therapy be avoided in patients with COPD at increased risk for arrhythmia (90, 97). Long-term azithromycin therapy may result in new azithromycin-resistant nasopharyngeal bacterial strains (94) and cause increased azithromycin resistance in sputum bacterial isolates after just 3 months’ treatment (100). A practical approach is to use macrolides in patients with ongoing exacerbations despite triple therapy (95). However, this strategy does not target a likely responder subgroup or address concerns regarding antibiotic resistance.
RCTs evaluating mucolytics have varied greatly in their inclusion criteria (e.g., presence of chronic bronchitis, use of inhaled treatments) and exacerbation definition. Nevertheless, a systematic review suggests an effect on exacerbation reduction (101). Important questions remain regarding the effect of mucolytics in non-Asian populations (102), at varying doses (103), and when associated to optimal concomitant therapies (104).
An FEV1-free approach appears reasonable (provided that the diagnosis is confirmed using spirometry), targeting pharmacotherapy toward symptoms (impact) and exacerbations (activity). These are clinically recognizable treatable traits (105). Personalized approaches targeting uncontrolled treatable traits can be further developed to include biomarker measurements that provide information on underlying mechanisms (endotypes) and/or disease activity. The historic and current approaches to COPD pharmacotherapy have used FEV1 and clinical phenotyping, respectively, to guide treatment choices (5); Figure 3 summarizes the evolution to a more personalized approach on the basis of treatable traits plus biomarkers.
Let us consider the example of persistent bacterial colonization (an endotype) associated with increased exacerbations (clinical phenotype, disease activity marker, and treatable trait); biomarker development to identify patients who would respond best to pharmacotherapies such as macrolides would be of value. Similarly, identifying patients with repeated exacerbations of a specific endotype (e.g., bacterial infection vs. eosinophilic inflammation) may allow more effective targeting of preventive treatments (i.e., bronchodilators ± macrolides vs. ICS-containing regimen). This may prove difficult, because exacerbation mechanisms can change from one exacerbation to the next. Another example is emphysema (clinical phenotype and treatable trait); the development of biomarkers, possibly sRAGE (39), may identify patients with greater disease activity who would benefit from future pharmacological treatments targeting specific mechanisms (endotypes) involved in tissue destruction.
COPD RCTs have not generally enrolled patients with GOLD stage I disease (FEV1 > 80% predicted). There is a high symptom burden in some patients with GOLD I disease (106) and some smokers without airflow obstruction (107). The efficacy of COPD treatments within this subgroup should be addressed to develop personalized approaches.
The new inhaled therapies for patients with COPD in recent years have been confined to existing classes (LAMA, LABA, ICS). Although it is disappointing that no novel classes have been introduced, there is scope to develop a more personalized use of these existing medicines within our current practice. This is helped by evidence from head-to-head studies of different classes (28, 71, 72, 77, 78), which are changing the way that we view bronchodilators and ICS. New evidence suggesting that LABA/LAMA combinations may be more effective than ICS/LABAs for exacerbation prevention make the differential diagnosis between asthma and COPD even more important (28), because ICSs remain the cornerstone of asthma maintenance therapy. Physicians should not label a patient as having asthma–COPD overlap without performing the required investigations.
In the near future, we need measurements of endotypes and disease activity for the development of COPD drugs with novel mechanisms of action. These drugs will likely only show a satisfactory benefit-versus-risk ratio in narrowly defined subgroups, and we need to develop the tools to define these subgroups.
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