The quality of hereditary haemochromatosis guidelines: A comparative analysis

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1 Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx xxx Available online at ScienceDirect ORIGINAL ARTICLE The quality of hereditary haemochromatosis guidelines: A comparative analysis Annick Vanclooster a,, David Cassiman a, Werner Van Steenbergen a, Dorine W. Swinkels b, Mirian C.H. Janssen c, Joost P.H. Drenth d, Bert Aertgeerts e, Hub Wollersheim e,f a Department of Hepatology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium b Department of Laboratory Medicine, Laboratory of Genetic Endocrine and Metabolic diseases, Radboud University Medical Centre, Nijmegen, The Netherlands c Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands d Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands e Academic Center for General Practice, KU Leuven, Belgium f Scientific Institute for Quality of Healthcare, Radboud University Medical Centre, Nijmegen Centre for Evidence-Based Practice, Nijmegen, The Netherlands Summary Background and objectives: Hereditary haemochromatosis (HH) is the most prevalent genetic liver disease, with an incidence of 1/200 to 1/400 in the Caucasian population. HH patients are treated by family physicians as well as different specialists. When left untreated or insufficiently Abbreviations: COPD, Chronic obstructive pulmonary disease; HH, Hereditary haemochromatosis; AGREE II, Appraisal of Guidelines, Research and Evaluation II; EASL, European Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; DUTCH, Netherlands Association of Internal Medicine (NIV), the Netherlands Society of Clinical Chemistry and Laboratory Medicine (NVKC) and Association of Laboratory Physicians (VAL); GRADE, Grades of Recommendation, Assessment, Development, and Evaluation system; CBO, Dutch Institute for Health Care Quality; ICC, Intraclass correlation; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; TS, Transferrin saturation; SF, Serum ferritin; LI, Liver iron; DM, Diabetes mellitus; PCT, Porfyria cutanea tarda; -Fp, Alfa-fetoprotein; ECG, Electrocardiogram; TSH, Thyroid-stimulating hormone; DEXA, Dual Energy X-Ray Absorption; MRI, Magnetic resonance imaging; R, Recommended; NR, Not recommended; PR, Partially recommended; NM, Not mentioned. Corresponding author. Tel.: ; fax: addresses: Annick.vanclooster@uzleuven.be (A. Vanclooster), david.cassiman@med.kuleuven.be (D. Cassiman), werner.vansteenbergen@uzleuven.be (W. Van Steenbergen), Dorine.swinkels@radboudumc.nl (D.W. Swinkels), M.Janssen@aig.umcn.nl (M.C.H. Janssen), J.Drenth@mdl.umcn.nl (J.P.H. Drenth), bert.aertgeerts@med.kuleuven.be (B. Aertgeerts), Hub.Wollersheim@radboudumc.nl (H. Wollersheim) / 2014 Elsevier Masson SAS. All rights reserved.

2 2 A. Vanclooster et al. treated, the complications can become life threatening. To support and evaluate qualitative care for HH, we evaluated and compared the available structured guidelines on screening, diagnosis and management of HH patients. Methods: Seven appraisers systematically reviewed the retrieved guidelines. The Appraisal of Guidelines Research and Evaluation II (AGREE II) was used to score and discuss the quality and reach consensus. The content of recommendations and the evidence behind them, were evaluated. Results: Three guidelines, developed by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and a DUTCH guideline were found. Fifty-seven percent of the recommendations were not shared between the guidelines, pointing to inconsistency of their content. Only two references supporting the recommendations were shared between all three guidelines. The AASLD guideline contains no information about management and follow-up. Moreover, the methodological quality of the AASLD guideline was rated insufficient, except for clarity and presentation (77%). Applicability of the guidelines was scored very low in all three (AASLD: 31%, EASL: 23%, DUTCH: 35%). The DUTCH guideline was judged best. Conclusions: Very poor consistency between available guidelines for HH hampers qualitative care and its evaluation. An updated high-quality and evidence-based guideline that covers follow-up and management of patients with HH is needed Elsevier Masson SAS. All rights reserved. Introduction Clinical practice guidelines are developed to improve efficacy, to reduce inappropriate practice [1] and to bridge the gap between research and practice [2]. The unrestricted availability of online databases as Medline and Embase should help to establish international consensus on evidence to support recommendations for clinical care, emanating in guidelines [3,4]. Several studies in chronic care, for example in the field of chronic obstructive pulmonary disease (COPD), show that guidelines can improve patient outcomes as well as the care process [5,6]. However, there is an increasing concern about variations of guideline quality and recommendations [7 9]. Guidelines on the same topic, especially when evidence is weak, often differ. Reasons for differences in recommendations are lack of sufficient evidence [10,11], difference in interpretation of evidence [12,13], unsystematic guideline development methods [14,15] and cultural factors [16,17]. Hereditary haemochromatosis (HH) is an autosomal recessive disorder, with a genetic prevalence of 1/200 to 1/400. It is very common and has an estimated carrier frequency of 1/10 in those from Northern European descent. The phenotype results from inappropriate accumulation of iron, resulting in end-organ damage [18]. Symptoms can be absent, but may also be debilitating; complications of the disease can be life threatening, as are diabetes mellitus, osteoporosis, cirrhosis, hepatocellular carcinoma [19]. The varying criteria for case definition, referral, diagnosis, interpretation of test results, follow-up, family screening approaches may lead to confusion in diagnosis and orientations for physicians, patients and their relatives. To support and evaluate qualitative care for HH, we studied the consistency in recommendations in the available guidelines, with emphasis on recommendations for treatment, follow-up, detection and management of complications of iron accumulation and the scientific evidence supporting these recommendations. We examined guidelines with a focus on three aspects: (1) the methodological quality of each guideline, examined with the international AGREE II (Appraisal of Guidelines for Research and Evaluation) instrument [20]; (2) the content of guideline recommendations; and (3) the use of evidence. Methods Selection of guidelines We searched for references to guidelines on HH in the Medline database as well as the National Guideline Clearinghouse using following MESH terms: haemochromatosis and practice guideline (publication type) or practice guidelines as topic (June 2013). We included only evidence-based guidelines with clearly defined recommendations from the last 10 years. If the guideline had been updated, the latest version was used. We included three guidelines from different professional organizations: European Association for the Study of the Liver (EASL), American Association for the Study of Liver Diseases (AASLD) and Netherlands Association of Internal Medicine (NIV), the Netherlands Society of Clinical Chemistry and Laboratory Medicine (NVKC) and Association of Laboratory Physicians (VAL) (DUTCH) [21 24]. Participants We established an expert panel of seven experts from five disciplines (two hepatologists, two internists, one general practitioner, one laboratory physician and one researcher)

3 The quality of hereditary haemochromatosis guidelines: A comparative analysis 3 from two European countries (Belgium and The Netherlands). All members participated in a critical appraisal of existing treatment guidelines by using AGREE II and all but one (M.C.H.J.) in a Modified-Delphi exercise to generate consensus. Evaluating the quality of the guidelines The quality of each guideline was determined by the expert panel using the AGREE II instrument [25]. This instrument is a tool that assesses the methodological rigor and transparency in which the guideline is developed. It is a 23-item tool comprising 6 quality domains. Each domain captures a unique dimension of the quality of guidelines (Table 1). Seven appraisers independently scored each item of the AGREE II instrument on a seven-point scale from one (strongly disagree) to seven (strongly agree). If elements were not reported, we tried to collect information from background documents of the guideline. The appraisers discussed any deviations in scores in a consensus meeting and resolved disagreements. One appraiser (M.C.H.J.) was unable to attend the consensus meeting and evaluated her results with the notes made during the meeting. An independent hepatologist (J.P.H.D.) led the consensus meeting. A quality score was calculated for each of the six AGREE II domains. The domain scores were calculated by summing up all the scores of the appraisers for the individual items in a domain and by scaling the total as a percentage of the maximum possible score for that domain. The resulting domain score is [(obtained score minimum possible score)/(maximum possible score minimum possible score)] 100%. Evaluating the content of recommendations Each topic from the EASL as well as the AASLD guideline was followed by clear written recommendations with a level of evidence. The DUTCH guideline summarized conclusions after each topic, mostly supported by a level of evidence, occasionally followed by recommendations (without level of evidence). If possible, the recommendation was linked to a corresponding conclusion with its level of evidence. If there was an important conclusion, but no corresponding Table 1 Overview of AGREE II domains and dimensions. Domain Dimension Scope and purpose (1) The overall objective(s) of the guideline is (are) specifically described (2) The health question(s) covered by the guideline is (are) specifically described (3) The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described Stakeholder involvement (4) The guideline development group includes individuals from all relevant professional groups (5) The views and preferences of the target population (patients, public, etc.) have been sought (6) The target users of the guideline are clearly defined Rigor of development (7) Systematic methods were used to search for evidence (8) The criteria for selecting the evidence are clearly described (9) The strengths and limitations of the body of evidence are clearly described (10) The methods for formulating the recommendations are clearly described (11) The health benefits, side effects, and risks have been considered in formulating the recommendations (12) There is an explicit link between the recommendations and the supporting evidence (13) The guideline has been externally reviewed by experts prior to its publication (14) A procedure for updating the guideline is provided Clarity of presentation (15) The recommendations are specific and unambiguous (16) The different options for management of the condition or health issue are clearly presented (17) Key recommendations are easily identifiable Applicability (18) The guideline describes facilitators and barriers to its application (19) The guideline provides advice and/or tools on how the recommendation can be put into practice (20) The potential resource implications of applying the recommendations have been considered (21) The guideline presents monitoring and/or auditing criteria Editorial independence (22) The views of the funding body have not influenced the content of the guideline (23) Competing interests of guideline development group members have been recorded and addressed

4 4 A. Vanclooster et al. recommendation, this item is indicated as concluded in Table 4. In addition, we selected text recommendations, which were not specifically described in the written recommendations. Recommendations for secondary haemochromatosis were excluded. The content analysis of the recommendations (Table 4) was done independently by two individuals (DC and AV). The EASL guideline, that contained a clear description of (text) recommendations, was used as a reference and compared to both other guidelines. If a recommendation was lacking in the EASL guideline but mentioned in one of the two others, this recommendation was added. Contradictions were discussed and solved by mutual agreement. Evaluating the evidence use We analyzed the shared references between the three guidelines to compare the use of evidence. Only recommendations on primary haemochromatosis were analyzed. We performed an analysis for those references used as evidence for the recommendations (called relevant references ). Subsequently, the degree of overlap of relevant references was calculated. In addition, we compared the use of similar evidence in the recommendations for screening, diagnosis and management of the three guidelines. We determined the overlap in evidence use with the following formula: [number of shared references/total number of different relevant references] 100%. The total number of different references = total number of (DUTCH + EASL + AASLD) references number of shared references. Results Selection of guidelines Three guidelines met our search criteria: 1 American (AASLD), 1 European (EASL) and 1 guideline from the Netherlands (DUTCH) (Fig. 1) [21 24]. All three guidelines covered three main topics: screening, diagnosis and management. Each topic has several subdivisions, e.g. clinical and biochemical features are listed in the category diagnosis, while phlebotomy and liver biopsy are mentioned in the management section (Table 4). The AASLD as well as the EASL guideline used the same grading scale for the quality of reported evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation system (GRADE). The DUTCH guideline used the grading scale from the Dutch Institute for Health Care Quality (CBO). The guidelines varied regarding length, the number of (relevant) references, recommendations and presentation of the recommendations (Table 2). Evaluating the quality of the guidelines Before the consensus meeting, the intraclass correlation coefficient between the three guidelines was As a result of the consensus meeting, the coefficient of the Figure 1 Selection of publications. agreement for all appraisers on the quality of the guidelines was very high (ICC agreement = 0.988) after discussion. Table 3 shows that the DUTCH guideline was appreciated with high-standardized domain scores of 70 95%, with the exception of applicability. All three guidelines had a high score on the domain clarity and presentation (77 87%). A (very) low appreciation was given to all other domains for the AASLD guideline. The EASL and DUTCH guideline were recommended or strongly recommended in the general judgment of the appraisers. There were large differences between the AASLD guideline and the DUTCH guideline in scope and purpose, stakeholders involvement, rigor of development and editorial independence (Table 3). The appraisers gave an average or high score to the EASL guideline, except for stakeholders involvement and applicability. In the applicability domain, potential organizational barriers and cost implications were largely ignored by the authors of the guidelines. For example, the DUTCH guideline describes an indication for MRI in patients with elevated iron parameters without p.cys282tyr homozygosity, but does not give any information about organizational or financial implications. The AASLD guideline contained minimal reference to the used methodology. There was no explicit description of the search methods, selection criteria for evidence nor reference to indication of health benefits, side effects and risks in the recommendations. Evaluating the content of recommendations A total of 39 different recommendations were compared between the AASLD, EASL and DUTCH guideline (Table 4). The levels of evidence can be compared between the AASLD and the EASL guideline, because the use of GRADE for reporting the quality of evidence. No comparison can be made with the DUTCH guideline, because they used conclusions

5 The quality of hereditary haemochromatosis guidelines: A comparative analysis 5 Table 2 Characteristics from the AASLD, EASL and DUTCH guidelines for hereditary haemochromatosis. Guidelines Publication year Pages Total references Topic Relevant references Level of evidence per According to Search period Search terms Databases AASLD Screening 17 Recommendation GRADE d a Haemochromatosis Medline Diagnosis 7 Management 8 EASL Screening 48 Recommendation GRADE 1966 March 2009 Not described b Medline Diagnosis 9 Embase Management 23 Cochrane Library DUTCH Screening 16 Conclusion CBO d 1949 middle 2005 c Available at CBO e Medline Embase Diagnosis 25 Cochrane Management 21 Library a No specific search period: articles from b Systematic literature review was based on four questions: (1) prevalence and (2) penetrance of C282Y homozygosity, (3) diagnosis and (4) management of HH. c 1949: oldest referred article. d See Appendix S1. e See Appendix S2.

6 6 A. Vanclooster et al. Table 3 Quality domain scores assessed with AGREE II for American, European and DUTCH guidelines for hereditary haemochromatosis. Standardized scores (%) AASLD EASL DUTCH Scope and purpose Stakeholders involvement Rigor of development Clarity and presentation Applicability Editorial independence Total 34 53,5 74 Figure 2 Shared references between the AASLD, EASL and DUTCH guidelines. instead of recommendations and used a different scoring system. As follows from Table 4, only 10 recommendations were entirely and seven recommendations partially similar between the guidelines (in grey). As a consequence, over 50% of the recommendations were not overlapping. We did not identify conflicting recommendations, however. The most striking result to emerge from Table 4 is that the AASLD and DUTCH guideline did not contain any recommendation on the follow-up of HH. For example, these guidelines do not include stipulations on monitoring of patients with arthralgia, monitoring of osteoporosis, monitoring of diabetes development, etc. The DUTCH guideline does feature a text recommendation about follow-up of patients with cirrhosis, however. Evaluating the evidence In total, 432 references were cited in the three guidelines. Only 12 relevant references were shared between the EASL, AASLD and DUTCH guideline, which translates in a shared score of 2.7%. Fig. 2 shows the shared relevant references between the three guidelines. Only a single reference was shared between the three guidelines within the screening item and another one in the management item, but none for diagnosis. The AASLD guideline does not describe an exact search period, but cites this as a formal review and analysis of the recently published world literature on the topic (Table 2). They included literature from 1980 until Discussion HH is a frequent disorder and can lead to life threatening complications when detected late or treated inadequately. Therefore, clear benefits for patients and society can be expected from high-quality detection, treatment and follow-up schemes. To support qualitative care for HH, and allow objective evaluation of the quality of care, we studied the methodological quality of available HH guidelines. In addition, we studied the consistency in the recommendations made in the available guidelines, with emphasis on recommendations made for treatment, follow-up, detection and management of complications. Finally, we also studied the scientific evidence supporting the recommendations made in the available guidelines. There was a large difference in quality of the guidelines. The methodological quality of the AASLD guideline was rated insufficient. Applicability was scored very low for all three guidelines. This may clearly hamper implementation of the recommendations made, in everyday clinical practice. Low scores on applicability have also been described in other guideline evaluations, and are possibly due to lack of an uniform approach, to organizational barriers and cost implications when applying the recommendations they make [26 29]. In other words, guideline developers and the professionals that are responsible for implementing the recommendations, are not necessarily similar. Also of note, the AASLD and DUTCH guidelines did not contain any recommendation on the detection or follow-up of HH-related complications (Table 4). With regard to the consistency of the recommendations, we found that less than half of the recommendations were shared between the guidelines. Weak, differing or lacking evidence has often been shown to underlie differences in guideline recommendations [10 13]. Many recommendations from the studied HH guidelines lack corresponding evidence or are based on expert opinion (Table 4). Also non-systematic guideline development [14,15] can complicate comparability between guidelines, as is probably the case here (see Fig. 2 showing poor overlap in references used). Especially the AASLD guideline was developed in an explicitly non-systematic way. Finally, cultural aspects, e.g. habits, the patients expectations, the structure of the healthcare system, seem to influence the selection of literature data and diagnostic and therapeutic recommendations [16], while variability in guidelines can also be attributed to differing author teams, differing nations and differing process development issues [29]. This study has several strengths. First, seven independent appraisers scored the three guidelines according to AGREE II with a high degree of agreement. Second, two independent researchers evaluated the (text) recommendations, which increases the validity of the findings. A potential limitation of our study is the contribution of one of the appraisers

7 The quality of hereditary haemochromatosis guidelines: A comparative analysis 7 Table 4 Content analysis of recommendations on screening, diagnosis and management of hereditary haemochromatosis. AASLD Recommendation EASL Recommendation degree a degree DUTCH Recommendation degree b Screening Population screening For HFE-HC patients NR 1 NR 1 NR c Family screening First-degree relatives R 1 R 1 R 2 No evidence family screening of C282Y/, H63D/H63D, H63D/ genotype patients NM NM R Risk group screening Porphyria cutanea tarda NM R 1 NM Chondrocalcinosis NM R 2 NM Unexplained arthritis or arthralgia NM NR 1 NR Hepatocellular carcinoma NM R 2 NM Type 1 diabetes mellitus NM R 2 R c Type 2 diabetes mellitus NM NR 1 NM Family history or suspected organ involvement R 1 NM NM Patients from liver clinics fasting TS and SF R c R i 1 PR 3 Genetic testing of all with SF and/or TS 45% R 1 R i 1 R Diagnosis Clinical Liver function disturbance R 1 R 1 NM Patients with suggestive findings combined of TS and SF R 1 R c R 3 Biochemical Determine fasting TS and SF (in a second stage) R c R i 1 PR c 3 Genetic Unexplained liver disease with TS NM R 1 R HH diagnosis requires C282Y/C282Y and TS or SF or LI NM R 1 NM C282Y/H63D and H63D/H63D with TS or SF or LI investigation of NM R 1 R 3 other causes Management Phlebotomy SF or LI R 1 R 1 R c Removing ml blood PR c,i R i 1 Concluded i 4 Removing blood weekly or every two weeks R i 1 R 1 Concluded i 4 Target levels SF: g/l R i 1 R c R i 4 Advanced fibrosis or cirrhosis R c R 2 R 2 Adequate hydration before and after phlebotomy NM R i 1 NM 24h-avoidance of vigorous physical activity NM R i 1 NM C282Y/C282Y phlebotomy without liver biopsy if SF < 1000 g/l and absence of ALT/AST elevation R i 1 NM NM

8 8 A. Vanclooster et al. Table 4 (Continued ) AASLD Recommendation EASL Recommendation degree a degree DUTCH Recommendation degree b Liver biopsy Offered to C282Y homozygous patients with SF > 1000 g/l, AST, hepatomegaly, or > 40 years to stage the degree of liver disease PR d 1 R 1 PR e 2 To diagnose HH NR 1 NR c NR 2 Examinations Transient elastography NM R c NM f MRI NM R c R c General Annual monitoring C282Y homozygotes without iron overload R c,g R i 2 PR c,h Hepatitis A and B immunization NM R i 2 NM Assessment for complications j before initiation phlebotomy PR c R 1 NM Routine follow-up during phlebotomy Cirrhosis: ultrasound and -FP/6 months to detect early tumor NM R 1 R c Diabetes mellitus: glucose control NM R 1 NM Arthralgia, arthritis: physical and radiological evaluation NM R i 1 NM Cardiac disease: 30% ECG abnormalities: follow-up ECG NM R 1 NM Endocrine disease: TSH, serum testosterone NM R 1 NM Osteoporosis: DEXA scan NM R 1 NM Monitoring for SF, TS and maintenance phlebotomy R i 1 R c R 3 Diet Dietary adjustments unnecessary avoiding vit C/iron supplements R 1 R c concluded 4 Avoiding excess alcohol intake R c R c R c Avoiding red meat NM NM concluded 4 Black tea intake during meal NM PR c concluded 4 AST: aspartate aminotransferase; ALT: alanine aminotransferase; TS: transferrin saturation; SF: serum ferritin; LI: liver iron; DM: diabetes mellitus; PCT: porfyria cutanea tarda; -Fp: -fetoprotein; ECG: electrocardiogram; TSH: thyroid-stimulating hormone; DEXA: dual energy X-ray absorption; MRI: magnetic resonance imaging; R: recommended; NR: not recommended; PR: partially recommended; NM: not mentioned. a Recommendation degrees for the AASLD and EASL guidelines were used according to the GRADE scales, 1 2 (strong-weak). b Recommendation degree for the DUTCH guideline, recommendations are conclusion-based with level of evidence according CBO, 1 4 (strong-weak). c Text recommendations. d Or compound heterozygous, AST or ALT, no age restriction for AASLD guideline. e To determine liver damage: SF > 1000 g/l. f Referred article in EASL from g Or compound heterozygous. h Every three years. i Unsupported/unreferred recommendation. j DM, joint disease, endocrine deficiency, cardiac disease, PCT.

9 The quality of hereditary haemochromatosis guidelines: A comparative analysis 9 (D.W.S.) in the development of the DUTCH guideline, which could cause bias towards a more positive evaluation of the DUTCH guideline at the individual assessment as well as the consensus meeting. Nevertheless, the four Belgian collaborators all considered the DUTCH guideline as showing the best overall quality, independent from the DUTCH collaborators before as well as after the consensus meeting. From our study, we conclude that the available HH guidelines can be improved in terms of methodological quality, consistency of recommendations and evidence base. The current situation hampers qualitative treatment and followup of HH patients and does not allow the extraction of robust parameters to evaluate quality of care for HH. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. 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