what is the oldest new idea to improve cf care

Ten years of comeback innovation in cystic fibrosis care

Accelerating implementation of biomedical research advances: critical elements of a successful 10 twelvemonth Cystic Fibrosis Foundation healthcare delivery improvement initiative

Costless

1. Bruce C Marshall1,
2. Eugene C Nelson2

1. ⁱCystic Fibrosis Foundation, Bethesda, Maryland, The states
2. ²Dartmouth-Hitchcock Medical Center and The Dartmouth Institute for Health Policy and Clinical Do, Lebanon, New Hampshire, U.s.

1. Correspondence to Dr B C Marshall, Cystic Fibrosis Foundation, 6931 Arlington Road, Bethesda, Doctor 20814, Us; bmarshall{at}cff.org

Abstract

Context: Scientific and therapeutic advances Remarkable biomedical research advances accept led to innovative and increasingly constructive therapies. We highlight several scientific milestones in elucidating the pathophysiology of cystic fibrosis (CF) and review the therapies that have become bachelor over the past 20 years.

Impact of the quality improvement initiative In 2002, the CF Foundation launched a multifaceted quality improvement initiative to accelerate comeback in CF care. Nosotros nowadays show of substantial improvement in process measures, such equally more consistent outpatient follow-up, and key medical outcomes, including survival, pulmonary function and nutritional condition.

Critical success factors We offering our perspective on factors critical to the success of the quality improvement initiative, including a compelling strategic program and the commitment of the CF Foundation to its implementation; the investment in edifice improvement capacity at CF intendance centres; the appointment of people with CF and their families every bit partners; and the integration of quality improvement into the existing CF care framework.

Directions for the next decade In addition to a continued investment in edifice and sustaining improvement capacity at CF intendance centres, and deeper patient engagement, we will accost the oppressive treatment burden. We volition also complement the measurement of clinical outcomes with patient reported outcomes and healthcare costs for a balanced assessment of the quality and value of care.

Conclusions Major advances in basic science and therapeutic development coupled with improvements in healthcare commitment have resulted in hitting gains in medical outcomes for people with CF.

Keywords

• quality improvement
• chronic disease management
• patient-centered care
• patient registry
• benchmarking

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Keywords

• quality improvement
• chronic disease management
• patient-centered care
• patient registry
• benchmarking

Introduction

The cystic fibrosis (CF) customs has benefited from remarkable biomedical enquiry advances, which have led to innovative and increasingly constructive therapies. We suggest that this success has been magnified and accelerated by the introduction of healthcare improvement strategies into the CF care model. Improved process measures including more consistent outpatient follow-upward, better vaccination rates, more systematic screening for co-morbidities and wider use of proven therapies have been associated with improvements in fundamental clinical outcomes such as survival, pulmonary part and nutritional status. We offering our perspective on the factors critical to the success of the quality comeback initiative and shut with our thoughts on directions for the upcoming decade.

Context: scientific and therapeutic advances

Unravelling the pathophysiology

At the time of Dr Dorothy Andersen's (figure one) early description of CF in 1938,1 the prognosis was dismal and the underlying pathogenesis was poorly understood. An astute clinical ascertainment of children with CF presenting with heat prostration during a torrid New York Metropolis heat moving ridge in August 19482 provided a clue to the pathogenesis. The discovery of strikingly elevated chloride and sodium levels in the sweat of individuals with CF by Paul di Sant'Agnese (effigy 2) and colleagues explained the increased risk of dehydration3 and eventually led to the diagnostic sweat chloride test.four Further inquiry showing chloride impermeability in the sweat duct5 and similar abnormalities in the airway epithelium6 linked the scientific findings to the clinical manifestations of the disease (meet box 1).

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Figure 1

Dr Dorothy H Andersen, accepting an award for her early on description of cystic fibrosis, from Robert Natal (right), president of the New York Affiliate of the National Cystic Fibrosis Foundation, and Victor Blitzer, former president, 1958. Library of Congress, Prints and Photographs Division, New York World Telegram and Sunday Collection.

The discovery of the CF transmembrane conductance regulator (CFTR) cistron and the major mutation (F508del) in 1989 by Drs Lap-Chee Tsui, Jack Riordan and Francis Collins (effigy 3) and colleagues7 was a pivotal milestone in unravelling the pathophysiology of this autosomal recessive disease. The CFTR poly peptide proved to be a regulated membrane anion channel,eight thus connecting the gene, protein and cellular abnormalities. Hope that this breakthrough would lead to a gene transfer cure faded with the daunting challenge of efficiently delivering the normal CFTR gene to airway cells without inducing inflammation.9

Box 1

Unravelling the pathophysiology: scientific milestones

• 1938: Early on description of the disease as distinct from coeliac disease

• 1948: Clinical presentation of cystic fibrosis patients with heat prostration

• 1953: Discovery of elevated sweat chloride

• 1963: Development of the diagnostic sweat chloride test

• 1983: Discovery of chloride impermeability in sweat ducts and airway epithelium

• 1989: Discovery of the cystic fibrosis transmembrane conductance regulator gene and major mutation (F508del)

Advances in pulmonary therapeutics

As the basic biology of the CFTR cistron and protein advanced, the CF community aggressively pursued the development of therapies targeting the pulmonary manifestations of the disease, the major cause of bloodshed. Several therapies were shown to improve pulmonary function and/or subtract pulmonary exacerbations (meet box 2). Inhaled dornase alfa10 and tobramycin solution for inhalation11 received The states regulatory approval in 1993 and 1997, respectively. Azithromycin for patients chronically infected with Pseudomonas aeruginosa12 and inhaled hypertonic saline13 were reported to be constructive in clinical trials in 2003 and 2006, respectively. Another inhaled antibiotic, aztreonam for inhalation solution,14 ,15 received United states regulatory approval in 2010. These chronic pulmonary therapies are recommended in testify based clinical practice guidelines16 ,17 and take been widely adopted at CF intendance centres.

Box 2

Advances in pulmonary therapeutics

• 1993: Dornase alfa, United states regulatory approving

• 1997: Tobramycin solution for inhalation, US regulatory blessing

• 2003: Azithromycin, published randomised controlled trial showing safety and effectiveness

• 2006: Hypertonic saline, published randomised controlled trial showing safe and effectiveness

• 2010: Aztreonam solution for inhalation, US regulatory approval

Targeting the basic defect

While these therapeutic advances were laudable, drugs targeting the bones defect were notably lacking. To address this void, the CF Foundation launched the Therapeutics Development Programme (TDP) in 1998 to attract the expertise and resources of pharmaceutical and biotechnology companies by lowering their risk of entering CF enquiry. In addition to financial support of TDP awardees via milestone driven grants, the Foundation contributes clinical and scientific knowledge of the disease, and access to the CF care center and clinical research networks. Success, every bit evidenced by regulatory approval of a drug, triggers a fiscal render to the Foundation to support CF inquiry and clinical programmes. Other voluntary health intendance organisations have emulated this innovative 'venture philanthropy' model18 created by Dr Robert J Beall (figure 4).

The first TDP collaboration, formed with Aurora Biosciences (subsequently caused by Vertex Pharmaceuticals) in 1999, funded high throughput screening of chemical libraries in search of CFTR modulators (correctors and potentiators). Correctors target the misfolding of CFTR protein which disrupts transport to the cell membrane, and potentiators target the defective gating of CFTR protein at the cell membrane. Ivacaftor, the initial output from this collaboration, is a potentiator that targets the gating defect acquired by the G551D mutation present in approximately 4% of individuals with CF in the USA. Clinical trials of ivacaftor showed marked improvement in medical outcomes as well as a hit subtract in sweat chloride values to below the standard diagnostic cut-off for CF,nineteen confirming CFTR as the drug target. The force of these findings led to rapid United states of america regulatory approval in 2012. Ivacaftor is now widely prescribed for eligible patients, and evidence suggests that it is highly effective in the clinical setting.20 The development path for ivacaftor provides a roadmap for other potential CFTR modulators, which could change the face of the disease.

Touch of the quality improvement initiative

Improvements in CF care commitment and medical outcomes kept step with the remarkable scientific and therapeutic advances. In 2002, the CF Foundation launched a multifaceted quality improvement initiative to advance comeback in CF care.21 The cornerstones of the initiative are described in detail elsewhere in this supplement and include leadership development, scientific approach to change, patient engagement and implementation of clinical practice guidelines. The data shown below are derived from CF Foundation'southward patient registry,22 which serves equally a rich resource to evaluate practise patterns and medical outcomes over time.

Procedure measures

A number of care process measures derived from guideline recommendations have shown improvement over the past decade. Quarterly follow-up is recommended for close monitoring of signs and symptoms, respiratory microbiology, pulmonary function and nutritional condition. The proportion of children six–17 years of age with four or more clinic visits, four or more than respiratory cultures and 2 or more pulmonary function tests increased from 25% in 2003 to 57% in 2012. Among children with suboptimal nutritional status (trunk mass index (BMI) <50th percentile for age), the per cent evaluated past a dietitian, increased from 78% in 2003 to 94% in 2012.

Regular clinical follow-up as well provides opportunities for preventive interventions and screening for comorbidities. The influenza vaccination rate for individuals with CF ≥6 months of age increased from 88% in 2006 (27.8% of patients with unknown vaccination status excluded from the analysis) to 94% in 2012 (16.3% of patients with unknown vaccination status excluded from the analysis). From 2002 to 2012, the prevalence of depression and osteoporosis for individuals with CF ≥eighteen years of age increased from 10.4% to 22.2% and from 3.7% to 8.v%, respectively, likely due to more systematic screening. Although the improvements in process measures are encouraging, the causal link to clinical outcomes cannot be clearly established absent a prospective trial.

Survival

The success of the CF intendance model is axiomatic in the dramatic improvement in survival from the 1960s when most children with CF did not reach school age.23 ,24 Accreditation of care centres across the United states of america in the 1960s, 1970s and 1980s, and the associated standardisation of multidisciplinary intendance, certainly contributed to the improved survival. Survival has continued to ameliorate, most notably over the past decade. Median predicted survival, calculated past life table analysis, increased from 29.iv (95% CI 28.4 to 30.8) years in 1992, to 31.three (95% CI 29.7 to 33.i) years in 2002, and to 41.1 (95% CI 37.4 to 43.one) years in 2012. About half of the CF patient population in the Usa is now 18 years of historic period or older.

Pulmonary function

Pulmonary office has also markedly improved (figure 5). A sceptic might fence that the pulmonary function improvement was simply due to the introduction of the chronic pulmonary therapies into clinical practise. However, we believe that the therapies and the quality improvement initiative were complementary drivers of improved outcomes. New therapies are often slow to diffuse into routine do without a promotional campaign and/or strategies to facilitate implementation. A number of CF care centres focused their comeback work on ensuring that the pulmonary therapies were prescribed for eligible patients.25 This likely contributed to the clinical adoption of the pulmonary therapies, peculiarly azithromycin and hypertonic saline (figure six), which do not have regulatory approving for their use in CF and are therefore not promoted to the CF care centres by pharmaceutical companies.

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Figure 6

The use of therapies in eligible patients from registry data is shown from 1994 to 2012. Explicit criteria for eligibility were developed from recommendations in published clinical practise guidelines.xvi ,17 Patients are included if they were prescribed the specific therapy at whatever encounter during the twelvemonth.

Nutritional outcomes

Many CF care centres focused on improving the nutritional condition of their patient population, outcomes which are much less likely to exist confounded by the introduction of the pulmonary therapies. In add-on to the improvement in BMI percentile for children (figure vii), remarkable improvement in height and weight for age percentiles has occurred over the past decade compared with previous decades (figures 8, nine). Newborn screening for CF, implemented in the great majority of states in the mid to late 2000s, may have contributed to the improved nutritional measures in younger children, merely not for the older children and adolescents. These information suggest that the quality improvement initiative contributed to the impressive gains in nutritional outcomes over the past decade.

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Figure vii

Cross exclusive analyses of registry information from 1992 to 2012 testify improved body mass index (BMI) percentiles. Calculated from 2000 US Center for Disease Control and Prevention reference values.25a

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Effigy 8

Cantankerous exclusive analyses of registry data from 1992 to 2012 show improved height for age percentiles. The 2012 information bear witness what appears to be a pubertal growth spurt, not axiomatic in the 1992 or 2002 information calculated from 2000 US Center for Affliction Command and Prevention reference values.^25a

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Figure nine

Cantankerous exclusive analyses of registry information from 1992 to 2012 evidence improved weight for historic period percentiles. Calculated from 2000 U.s.a. Center for Illness Control and Prevention reference values.^25a

Middle level outcomes

The touch on of quality comeback is near apparent in the centre level data. Figure x shows pulmonary and nutritional outcomes for children with CF. Each dot represents the median values for a CF care eye. The magnitude of the overall alter in median values from 2002 to 2012 (forced expiratory volume in 1 s (FEV₁) per cent predicted +6.0; BMI percentile +10.5) is clinically significant. Past 2012, FEV_one per cent predicted for many centres approached or exceeded 100%, diminishing the potential for further improvement (ie, 'ceiling upshot'). Many, but not all, centres that engaged in and sustained quality improvement activities have shown significant comeback in pulmonary and/or nutritional outcomes. For example, the CF care centres reporting their work in this supplement have achieved substantial gains, particularly in nutritional outcomes (see table 1).

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Table 1

Comeback in pulmonary and nutritional outcomes from 2002 to 2012

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Figure x

Forced expiratory book in 1 south (FEV₁) versus trunk mass index (BMI) percentiles for patients aged half-dozen to 17 years. Each pink dot represents the median values for BMI percentile and FEV₁ per cent predicted for children at an individual intendance centre in 2002, and each blue dot represents the median values in 2012. The red and black lines show the overall population medians for BMI percentile and FEV_ane per cent predicted for 2002 and 2012, respectively. The dots with hatched marks (× −2002 and + −2012) prove the care centres reporting their improvement activities in this supplement. Their improvement in outcomes compared with all other care centres is shown in table 1.

In summary, given the complexity of the healthcare system and the introduction of new therapies, a causal link between quality improvement and improved national level outcomes cannot exist proven. However, the circumstantial bear witness suggests a substantial impact and supports the value of this approach for other chronic diseases.

Critical success factors

Nosotros identified v factors critical to the success of the quality improvement initiative (box 3) supported by the strategic investment of the CF Foundation. The multidisciplinary CF care model with peer review and a long continuing patient registry21 ,26 provided fertile basis for this work. The importance of these existing assets should not be overlooked. The strategic program coupled with the delivery of the CF Foundation to its implementation led to an investment in building improvement capacity at CF care centres and the engagement of people with CF and their families as partners in the improvement piece of work.

Box three

Critical success factors

1. Compelling strategic plan (ie, opportunity statement)

2. Commitment of the Cystic Fibrosis Foundation to implementation

3. Investment in edifice improvement capacity at cystic fibrosis care centres

4. Focus on engaging people with cystic fibrosis and their families

5. Integration of quality improvement into the cystic fibrosis care framework

Factors 1 and two: compelling strategic plan and delivery to implementation

Acknowledging the wide variation in outcomes across the care centre network and engaging external improvement experts in the strategic planning procedure took courage on the part of CF Foundation leaders. The Opportunity Statement that resulted from the strategic planning process stated the vision of exemplary care at all CF intendance centres and created a sense of urgency for improvement. Cardinal strategies and worthy goals provided a focus for comeback activities.21 Credible clinical leadership at the CF Foundation coupled with comeback expertise at Dartmouth ensured high visibility of the initiative. Learning and Leadership Collaboratives were organised (see beneath) and a Quality Comeback Grants Programme was established to support innovative work. Progress was regularly featured at the Almanac North American CF Conference, leaving no dubiousness nigh the CF Foundation'south commitment.

Factor 3: investment in building comeback capacity at CF care centres

Godfrey et al27 describe the primal elements of the year long CF Foundation sponsored Learning and Leadership Collaboratives, an important machinery for engaging CF care centres in quality improvement. We realised that reaching over 110 accredited care centres (comprised of over 250 distinct paediatric, developed and affiliate programmes) would take considerable fourth dimension and resource. We initially focused on recruiting clinical leaders in the customs and searched for early success stories that could exist shared peer to peer. The development of coaches to support the teams participating in the collaboratives allowed us to reach more intendance centres faster. By furthering the knowledge and experience of the coaches, we garnered strong advocates for quality improvement and enhanced the sustainability of comeback at their centres.

Benchmarking visits to high performing centres demonstrated the importance of factors other than the technical delivery of care. Optimal outcomes at CF care centres were associated with constructive leadership and team dynamics, close contact with patients and families, loftier expectations, and a proactive and consistent practice approach.28 These findings validated our focus on developing the comeback capabilities of frontline CF care teams.

The major impact of the unexpected departure of an experienced CF dietitian was an incidental finding at ane of the benchmarking visits. This observation led to the cosmos of mentoring programmes to pair an apprentice new to CF care with an experienced mentor in the same subject area from another care centre. Individual goals with a focus on improving intendance processes and outcomes are established for each amateur prior to a site visit to the mentor's CF care centre. These highly successful programmes,29 at present operational in several disciplines, foster the development of communities of practice30 and facilitate cross pollination of ideas for comeback.

Cistron 4: focus on engaging people with CF and their families

The perspective and practical knowledge of individuals with CF and/or parents on the teams that participated in a Learning and Leadership Collaborative enriched the improvement work and motivated the clinicians. Patient/family advisory boards were established at many CF care centres to gain broader input on improvement opportunities. Individuals with CF and/or parents were also invited to serve on clinical do guidelines committees, contributing to development of recommendations for care and complementing local efforts to improve intendance at their own CF centres.31

We recognised that achieving optimal outcomes required a potent partnership between people with CF and healthcare professionals. People with CF and their families consent to the collection of their data for the patient registry, so they, as partners, should have access to the centre level consequence measures. Schechter et al26 draw our path to data transparency and the public report of outcomes and process measures on the CF Foundation website (http://www.cff.org). To put it only, it became clear that it was the right affair to do and it would likely help the states accelerate improvement.

Gene 5: integration of quality improvement into the CF care framework

The integration of quality improvement into the existing CF care framework ensured sustainability. The members of the Eye Committee broadened their mission argument to embrace 'fostering exemplary care' as well equally ensuring that centres met accreditation standards. A report on quality comeback activities was required in almanac progress reports from care centres and at accreditation site visits. Quality award winners were selected past the Centre Committee and publicly recognised at the North American CF Briefing. Participation in quality improvement has at present become an expectation, driven more by the CF community than past central leadership.

Directions for the upcoming decade

Substantial progress has been fabricated since Andersen's clarification of CF, but much piece of work remains. While the improvement in clinical outcomes is remarkable, life expectancy is notwithstanding decades below that of the full general population. This highlights the need for additional CFTR modulators, and the CF Foundation is investing significant resources in facilitating the development of these drugs. We are both realistic and optimistic almost the challenges ahead. To ensure that people with CF fully benefit from these potential illness modifying therapies, we remain committed to the vision of exemplary care for all people with CF.

Directions for the upcoming decade are listed in box iv. We remain firmly committed to an ongoing investment in building and sustaining improvement chapters at CF care centres and deeper patient engagement. We will also accost a hidden toll of improved outcomes—that is, the oppressive treatment burden for individuals with CF—by: (one) gaining deeper knowledge of the challenges that individuals with CF and families face in adhering to the recommended treatment regimen and (ii) applying comparative effectiveness research methodologies to the registry data. Finally, we plan to complement the registry data with patient reported outcomes and cost outcomes for a broader and more balanced cess of the quality and value of CF care.

Box iv

Directions for the upcoming decade

• Develop cystic fibrosis care centres as patient centred medical homes

• Deeper patient engagement

• Address the handling burden

  • Comparative effectiveness research

  • Barriers to adherence

• Develop metrics to provide a balanced cess of quality and value of care

CF care centres as patient centred medical homes

Nosotros continue to back up the development of the CF care centre teams by providing opportunities to participate in improvement collaboratives, leadership development and mentoring programmes. Building on the success of improvement work inside CF care centre microsystems, we are likewise focusing on improving interactions with other related microsystems.32 For instance, CF related diabetes is a highly prevalent comorbidity33 associated with increased bloodshed and increased treatment burden. The care of an private with CF related diabetes requires coordination between the CF care center microsystem and an endocrinologist and care team in another microsystem. A well thought out referral plan, communication programme and role definition for the two interdependent microsystems are of import to achieve optimal outcomes.

We aspire to seamless integration within CF care centres (ie, between paediatric and adult CF programmes, and between inpatient and outpatient units) and with interfacing subspecialists and programmes (eg, state newborn screening programmes and lung transplant programmes). We envision the CF intendance eye equally the patient centred medical home34 for the lifelong journey of the individual with CF and his or her family, encompassing the various developmental stages from infancy through adulthood and clinical treat their CF and associated comorbidities.

Deeper patient engagement

A recent editorial in Health Affairs referred to activated engaged patients as 'the blockbuster drug of the century',35 pointing out the association with amend outcomes. Indeed, the 'vox of the patient and family' is of import in all that nosotros do. At the national level, this includes leadership on the CF Foundation'due south Board of Trustees, membership on guidelines committees and participation in clinical research processes. At the care centre level, this involves membership on comeback teams and patient/family advisory boards. At the individual level, this includes shared determination making past people with CF and their families in conjunction with their CF care centre healthcare professionals.

Nosotros adult, validated and field tested an experience of care survey36 to provide another mechanism for patient and family input on the quality of their care. Nosotros have found that care middle level survey results showing strengths and weaknesses compared with results from peer care centres will identify improvement opportunities in service related aspects of intendance delivery. The infrastructure needed to deploy this survey nationally provides the opportunity to collect additional patient reported consequence measures.

Addressing the treatment burden

The daily decisions of individuals with CF and their families about their medical regimen impact on clinical outcomes. Clinicians cannot accurately predict which patients are struggling to execute their dwelling house based medical regimen and patients are hesitant to report this information.37 Opportunities to identify and address challenges are missed. Nosotros are developing a patient engagement initiative to (1) identify the obstacles that individuals with CF and families confront in successful self-management and (2) equip people with CF, their families and healthcare professionals with the noesis, skills and resource to overcome these obstacles.

Nosotros are also applying comparative effectiveness research methodologies to the patient registry data to appraise the impact of specific therapies and combinations of therapies. Given the inherent limitations of observational information, retrospective registry analyses may crave validation in prospective trials. Nosotros are testing the feasibility of embedding pragmatic, cost effective clinical trials within the registry.38

The long term goal is to make up one's mind an optimal medical regimen for individuals with CF that is feasible to execute.

Counterbalanced assessment of quality and value of CF care

Nosotros are planning a comprehensive analysis of the price of intendance, including direct healthcare expenditures, and indirect costs such as days lost from school or work. Collectively, the clinical outcomes, patient reported outcomes and cost outcomes will provide a broader and more balanced assessment of the quality and value of CF care.39 This information will position the Foundation to better sympathise what aspects of care and which therapies drive improved outcomes in anticipation of the emerging value based approach to healthcare delivery and payment.

In summary, major advances in bones scientific discipline and therapeutics evolution coupled with improvements in healthcare commitment take resulted in striking gains in medical outcomes for people with CF. A devastating illness that took the lives of young children in the past has evolved to a challenging, but manageable, chronic disease. CFTR modulators hold the promise of dramatically extending the length and quality of life for individuals with CF. Incorporation of quality improvement into the CF care model has systematised continuous learning and comeback into a learning health system40 to assist people with CF and their families, and the CF healthcare professionals that serve them.

Acknowledgments

We gratefully admit the leadership and support of Bob Beall and Preston Campbell at the CF Foundation; the generous sharing of wisdom and feel by Brent James, Don Berwick and Paul Batalden; the too numerous to count contributions of Gerry O'Connor, Hebe Quinton, Margie Godfrey and Kathy Sabadosa at Dartmouth; the dedication of healthcare professionals at CF intendance centres across the The states; and, most chiefly, those whom we serve, people with CF and their families.

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Source: https://qualitysafety.bmj.com/content/23/Suppl_1/i95