aace guidelines american association of clinical endocrinologists

270 ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010

AACE Guidelines

Address correspondence and reprint requests to Dr. Jeffrey I. Mechanick, 1192 Park Avenue, New York, NY 10128. E-mail: [email protected].

© 2010 AACE.

AMERICAN AssOCIATION Of ClINICAl ENDOCRINOlOgIsTsPROTOCOl fOR sTANDARDIzED PRODuCTION

Of ClINICAl PRACTICE guIDElINEs—2010 uPDATE

Jeffrey I. Mechanick, MD, FACP, FACE, FACN; Pauline M. Camacho, MD, FACE;

Rhoda H. Cobin, MD, MACE; Alan J. Garber, MD, PhD, FACE;

Jeffrey R. Garber, MD, FACP, FACE; Hossein Gharib, MD, MACP, MACE;

Steven M. Petak, MD, JD, FACE; Helena W. Rodbard, MD, FACP, MACE;

Dace L. Trence, MD, FACE

2010 AACE CPg Protocol, Endocr Pract. 2010;16(No. 2) 271

CliniCAl PrACtiCE GuidElinEs subCommittEE

ChAir

Jeffrey I. Mechanick, MD, FACP, FACE, FACN

Pauline M. Camacho, MD, FACERhoda H. Cobin, MD, MACE

Alan J. Garber, MD, PhD, FACEJeffrey R. Garber, MD, FACP, FACE

Hossein Gharib, MD, MACP, MACESteven M. Petak, MD, JD, FACE

Helena W. Rodbard, MD, FACP, MACEDace L. Trence, MD, FACE

sPECiAl rEviEwErs

Mor Peleg, PhDWael Haddara, MD

272 2010 AACE CPg Protocol, Endocr Pract. 2010;16(No. 2)

ABSTRACT

In 2004, the American Association of ClinicalEndocrinologists (AACE) published the “Protocol forStandardizedProductionofClinicalPracticeGuidelines,”whichwastobeimplementedinforthcomingclinicalprac-ticeguidelines(CPG).Thisprotocolformallyincorporatedsubjective factors and evidence-based medicine (EBM)methodsthattightlymappedevidencelevelstorecommen-dationgrades.Auniformpublicationtemplateandmulti-levelreviewprocesswerealsooutlined.SevenCPGhavebeensubsequentlypublishedwithuseofthis2004AACEprotocol.Recently,growingconcernsabouttheusefulnessofCPGhavebeenraised.Thepurposesofthisreportaretoaddressshortcomingsofthe2004AACEprotocolandtopresentanupdated2010AACEprotocol forCPGdevel-opment.AACECPGaredevelopedwithoutany industryinvolvement.Multiplicitiesofinterestsamongwritersandreviewers thatmight compromise theusefulnessofCPGareavoided.Threemajorgoalsareto(1)balancetranspar-ently the effect of rigid quantitativeEBMmethodswithsubjectivefactors,(2)createalessonerous,lesstime-con-suming,andlesscostlyCPGproductionprocess,and(3)introduce an electronic implementation component. Theupdated2010AACEprotocolemphasizes“informedjudg-ment”andhybridizesEBMdescriptors(studydesigntype),qualifiers (study flaws), and subjective factors (such asrisk,cost,andrelevance).Inaddition,byfocusingonmorespecifictopicsandclinicalquestions,theexpertevaluationandmultilevelreviewprocessismoretransparentandex-peditious.Lastly,thefinalrecommendationsarelinkedtoanewelectronicimplementationfeature.(Endocr Pract. 2010;16:270-283)

Abbreviations:AACE = American Association of ClinicalEndocrinologists; CIG = computer-interpretableguidelines;CPG=clinicalpracticeguidelines;DOE= disease-oriented evidence;EBM = evidence-basedmedicine;GRADE =Grading ofRecommendations,Assessment,Development,andEvaluation;POEMS=patient-orientedevidencethatmatters

INTRODUCTION

In 2004, the American Association of ClinicalEndocrinologists (AACE) published the “Protocol forStandardizedProductionofClinicalPracticeGuidelines”(“2004AACEprotocol”)(1).Thatreportoutlined(1)theneed for evidence-based medicine (EBM) clinical prac-tice guidelines (CPG), (2) attributes of successful CPG,(3) a document template, (4) a specificmethod for evi-dence rating, incorporation of subjective variables, andtransparent formulation of recommendation grades, and

(5)arigorousmultilevelreviewprocess(1).Themandatefor thisdocument resulted from the increasednumberofAACECPG being publishedwithout a consistentmeth-odologic approach to provide anEBM recommendation.ThemajorissuesconfrontingAACECPGtaskforcesbe-fore 2004 were related to the controversies surroundingvariousEBMmethodsandhowtodistinguishEBMCPGfromothertypesofpublications,suchas“whitepapers,”clinicalalgorithms,roadmaps,consensusreports,opinionpapers,positionpapers,conferenceproceedings,technicalreviews, and reviewarticles.Before the existenceof the2004AACEprotocol,therewere19publishedAACECPGdocuments,ofwhich18wereconsensusreports—leavingonly 1 that used EBM technical review procedures (2).Subsequently,andaftera1-yearhiatustoreengineerCPGalreadyinprogress,7AACECPGwerepublished,allofwhichwereinstrictadherencewiththe2004AACEproto-col(Table1). Since 2004, important advances have been madein the area of CPG development. First, and probablymost importantly, is the popularization of the Gradingof Recommendations, Assessment, Development, andEvaluation(GRADE)system,whichhasbeenextensivelydiscussedintheliterature(3-12)andsubsequentlygarneredacceptancefromahostofmedicalsocieties,includingTheEndocrineSociety(13-15).AttributesoftheGRADEsys-temandotherEBMmethodologies(3-26)areoutlinedinTable2.Afterareviewofthesemethodologies,however,itwouldappearthatanoptimalCPGstrategymightnotbeentirelyevidence-based.Hence,animprovedCPGwouldmerge the elements of scientific substantiationwith ele-ments of transparency, intuitiveness, subjective factors,andrelevance.Inaddition,shortcomingsofevidence-basedmethodsshouldbeaddressed,suchasbeingtoocomplex,usingimpreciseterms(“semanticimprecision”),andbeingtoocostlyandlabor-intensivetoadaptandimplement. What constitutes the major difference between the2004AACEprotocolandothercurrentCPGprotocolsistheEBMmethodology.The2004AACEprotocolEBMmeth-odologywasoutlinedinTable2oftheoriginalreference(1)andisbasedonsimilarevidenceratingsandrecommen-dationgradesusedbytheAmericanDiabetesAssociation,the National Heart, Lung, and Blood Institute, and theAmerican Gastroenterological Association. Furthermore,itincorporatesmanyoftheattributesofotherCPGmeth-odologiessummarizedinTable2,herein.The2004AACEprotocol incorporates 4 intuitive evidence levels (strong,intermediate,weak,ornone)basedonresearchmethodol-ogyandstressesanexplicitandrigidnumericaldescriptor.TheseevidencelevelsarethendiscussedamongtheCPGauthors,andvarioussubjectivefactorsareincorporatedasneeded,suchasrisk-benefitanalysis,cost-benefitanalysis,clinicalrelevance,andothers.Afinalquantitativerecom-mendationgradeforDOINGanactionorNOTDOINGanaction is thendetermined.This is almostalways linearly


mappedtothebestevidencelevel.Anydeviationsinthismapping are explicitly described and explained.The ad-vantage of this evidence rating-grade recommendationprotocol is the intuitive simplicity (strong, intermediate,weak,ornone). Growing criticisms still surroundCPG in themedi-calliterature.Importantissues,suchascost-containment,geographicvariationsinresourceavailability,industryin-volvement,conflictsormultiplicitiesofinterest,bias,pau-cityof credentialedauthors, and time limitations,plagueprofessional medical societies and produce CPG resultsthatmaynotbecredibleorreproducible(27).Thissitua-tioncreatesconfusionandmitigatestheintendedbenefitofCPG:tofosteraconsistentpracticeofhigh-qualitymedi-cine.Inaddition,thenotionthatevidencemustberatedinaccordancewithsomerigidhierarchymightbemisguided.Forexample,inarecentarticleinThe Lancet,Rawlins(28)pointedoutthatthepresumed“goldstandard”ofclinicalevidence—a randomized controlled trial—hasmany pit-falls.Foremostamongthesepitfallsarenongeneralizabil-ityandoverdependenceonnon-Bayesianstatisticalanaly-sis(seeAppendixforGlossaryofTerms).

Even more problems exist. Systematic literaturesearchesaresubjecttostudypublicationandreportingbi-ases,inwhichmedicaljournalsaremorelikelytopublishstudies with positive findings rather than negative find-ings (29,30).Other issues thatmitigate clinical evidenceinmedicaldecisionmakingarestoppingrandomizedcon-trolled trialsearlybecauseofapparentbenefit (31),pooroverallqualityofmeta-analyses(32,33),failuretoincludeadequate intent-to-treat analysis (30,34), allocation con-cealment(randomization),andappropriate“blinding”(30).Tricocietal(35)highlightedtheimpactanddominanceofflawedand“weak”studiesonCPG.Onanalysisoftheevo-lutionofCPGrecommendationsbytheAmericanCollegeofCardiologyandAmericanHeartAssociation,theycon-cludedthatimprovedCPGmethodologieswillneedtoad-dresstheeffectofasurplusoflowerlevelsofevidence. Current protocols for literature searching may alsofail to account for complex interactions amongmultipleinterventions. Additionally, there are complexities thatresult from social networks among caregivers and otherclinicalpracticeidiosyncrasiesthataccountfordifferencesbetween “real-world” outcomes and “proof-of-concept”

Table 1American Association of Clinical Endocrinologists (AACE)

Clinical Practice Guidelines Published Since 2004 andin Strict Adherence With the 2004 AACE Clinical Practice Guidelines Protocola

Year Title Reference

2006 AACE/AMEMedicalGuidelinesforClinicalPracticefor Endocr Pract.2006;12:63-102 theDiagnosisandManagementofThyroidNodules

2006 AACEMedicalGuidelinesforClinicalPracticeforthe Endocr Pract.2006;12:193-222 DiagnosisandTreatmentofHypertension

2006 AACEMedicalGuidelinesforClinicalPracticeforthe Endocr Pract.2006;12:315-337 DiagnosisandTreatmentofMenopause

2007 AACEMedicalGuidelinesforClinicalPracticeforthe Endocr Pract.2007;13(suppl1):3-68 ManagementofDiabetesMellitus

2008 AACE/TOS/ASMBSMedicalGuidelinesforClinical Endocr Pract.2008;14(suppl1):1-83b

PracticeforthePerioperativeNutritional,Metabolic,and NonsurgicalSupportoftheBariatricSurgeryPatient

2009 AACE/AAESMedicalGuidelinesfortheManagementof Endocr Pract.2009;15(suppl1):1-20b

AdrenalIncidentalomas

2009 AACEMedicalGuidelinesforClinicalPracticeforGrowth Endocr Pract.2009;15(suppl2):1-29b

HormoneUseinGrowthHormone-DeficientAdultsand TransitionPatients—2009update

aAAES=AmericanAssociationofEndocrineSurgeons;AME=AssociazioneMediciEndocrinologi;ASMBS=American SocietyforMetabolic&BariatricSurgery;TOS=TheObesitySociety. bPublishedonlineonly(www.aace.com).


Table 2Attributes of Various Evidence-Based Methodologies Used for Clinical Practice Guidelinesa

Methodology Positive attributes Negative attributes References

ACC/AHA Highlydetailedmethodology 4×3matrixof“sizeoftreatmenteffect” 16,17 ×“estimateofcertainty,”whichmapsto recommendationgradesA-C;is nonintuitiveandconfusing ACCP Linksmethodologicstrengthwith FinalgradehybridizesRBAwith 18 high-priorityRBA;15-year methodology(matrix1-2×A-C+);is evolutionandhighlyvetted nonintuitiveandconfusing AGREE Validatedinstrument Surveyandconsensusamongwritersand 19 notanapriorievidencerating;primarily subjective ANHMRC Relevancehaspriorityoverstrength De-emphasizesmethodology(even 20 ofevidence though6ELs);noeffectofRBAor costs GRADE LinksELswithrecommendation Nonintuitivemappingoffullspectrumof 3-15 grades;highlyvettedandalso 4evidencelevelsto2(strongorweak) validatedinliteratureandamong recommendationgrades;costlyandlabor- severalprofessionalmedical intensivetoimplement societies;addressedshortcomings ofITTanalysis,randomization, andblindinginRCTs OCEBM Detailedevaluationofevidence Highlycomplexanalysisbasedon4 21 parametersproducing10levelsmapping to4grades;noinputfromRBA,cost, orrelevance,andmappingalgorithmnot transparent SIGN Validated,reproducibleELswith Unstructuredrecommendationgrades;not 22 questionnaire;abletodifferentiate reproducible designsbasedonthestudy question USPSTF TransparentmappingofELsto Complexmultilevelanalysis;inadequate 23-25 recommendationgrades;includes fordiagnosticquestions;doesnot RBAandsubjectivefactors incorporateindividualpatientfactors USTFCPS Manykindsofevidenceincludedin Complex;notveryreproducible 26 finalELs,whichmapdirectlyto recommendationgrades(goodfor publichealthquestions)

aACC/AHA=AmericanCollegeofCardiology/AmericanHeartAssociation;ACCP=AmericanCollegeofChestPhysicians; AGREE=AppraisalofGuidelinesforResearchandEvaluation;ANHMRC=AustralianNationalHealthandMedical ResearchCouncil;ELs=evidencelevels;GRADE=GradingofRecommendations,Assessment,Development,and Evaluation;ITT=intent-to-treat;OCEBM=OxfordCentreforEvidence-BasedMedicine;RBA=risk-benefitanalysis; RCTs=randomizedcontrolledtrials;SIGN=ScottishIntercollegiateGuidelinesNetwork;USPSTF=UnitedStates PreventiveServicesTaskForce;USTFCPS=UnitedStatesTaskForceonCommunityPreventiveServices.


outcomes. Incorporation of other sources of complexity,physiologicandpharmacologic,isnowbeingaddressedbyusingasystemsbiologyapproachtoclinicalmedicine(seeAppendix).Simplytypingkeywordsintoasearchengine,andthenperformingananalysis,willpotentiallymissim-portant,clinicallyrelevantcomplexinteractions.Shepperdetal(36)examinedthisproblemandproposedtheformu-lationofmiddle-rangetheorytoguideliteraturesearching(seeAppendix). Systematicliteraturesearchingshouldalsobeabletogauge clinical relevance (37-40). “Disease-oriented evi-dence”(DOE)—researchfocusingonintermediateorsur-rogate outcomes—dominates the medical literature andarguablymisinformsclinicaldecisionmaking(36).Thisisdistinguishedfrom“patient-orientedevidencethatmatters”(POEMs),inwhich,withlittleextrapolation,clinicianscaneasilyderiveinformationaboutdiagnostic,therapeutic,orpreventiveproceduresthathelppatientslivelongerorbet-ter (37). POEMs is considered highly relevant and validinformation. Examples in the endocrinology literatureinclude(1)fluoridetherapyincreasingbonemineralden-sity in postmenopausalwomenwith osteoporosis (DOE)versus fluoride therapy increasing nonvertebral fractures(POEMs)and(2)weightgainoccurringinpatientsintheUnitedKingdomProspectiveDiabetesStudy(exceptthosetreatedwithmetformin) (DOE)versusqualityof lifenotbeingaffected,positivelyornegatively,bytightbloodglu-cosecontrol(POEMs)(36).Althoughvariouspositionpa-perssupportingtheuseofPOEMshavehadlittleeffectonthepredominanceofDOEsinthemedicalliterature,thesepositionpapersraiseavalidpointthatCPGneedtoberel-evanttoactualclinicalproblems.Furthermore,byincorpo-ratingPOEMs,CPGmoveclosertotrulyhybridizingEBMwithmedicalhumanism(41).

ThE UPDATED 2010 AACE PROTOCOl

Currently, chairpersons and primarywriters activelyinvolvedinAACECPGtaskforceshavehadseveralyearsofexperiencewiththe2004AACEprotocol.Threegeneralcategoriesofshortcomingshavebeenarticulatedandserveastheimpetusfortheupdated2010AACEprotocol:meth-odology,reviewprocess,andimplementation.

The 4-Step EBM Methodology TheentireAACECPGdevelopmentprocess is con-ductedfreeofindustryinvolvement.OncetheCPGtopicisassigned,thechairpersonandprimarywritersareiden-tified.Thenmiddle-rangetheoriesaregeneratedthatwillguidethesystematicliteraturesearch.Oncethishasbeencompleted,thereare4sequentialstepsintheintegrationofclinicalevidenceintorecommendationgrades:

• StepI:evidenceratingbasedonmethodology• StepII:analysisofevidenceandidentificationofsub-

jectivefactors• StepIII:phrasing,determininglevelofconsensus,and

alphabeticgradingofrecommendations• StepIV:appendingqualifierstorecommendations

In the first step, credentialed experts on thewritingcommittee assign numerical and semantic descriptors tothe clinical evidence (Table3). In the second step, com-ments are provided regarding evidentiary strengths andweaknesses(Table4).Inthethirdstep,recommendationsarephrasedanddiscussed, levelsofconsensusaredeter-mined, and recommendation grades are conferred (Table5).Relevantdissentingopinionscanbebrieflyandexplic-itlyprovidedintheAppendixsectionoftheCPG.Therec-ommendationphraseologywillbeengineeredinthe2010AACEprotocoltocreateaclinicalalgorithmthatreflectstheprocessflowoftheclinicalencounterandcanbeusedintheelectronicimplementationcomponenttoreduceer-rors(42,43).Nodesintheclinicalalgorithmwillbenum-bered and then explicitly linkedwith graded recommen-dationsintheExecutiveSummaryandtheevidencebaseintheAppendixsectionoftheCPG(44,45).Inthefourthandfinalstep,miscellaneousqualifiersareconsideredthatwere not incorporated as subjective factors to determinetherecommendationgradebutarestilldeemedimportant(Table6).An explicit descriptionof thesemiscellaneousattributesoftheevidencebaseandthesubsequentexpertdiscussion are provided in theAppendix section of theCPGinanefforttooptimizetransparency. Anoptionalproceduralstepmaybeappendedtotherecommendations in step IV if the experts conclude thatalternative recommendations can be formulated. Thesealternatives may be due to variations of resource avail-ability and cultural factors in different geographic areas.AnalternativegradedrecommendationwouldbeprovidedintheExecutiveSummary,andtherationalewouldbein-serted in theAppendix. Inotherwords,globallyrelevantrecommendation“cascades”(46)areproduced,whichcanbroadentheutilityandapplicabilityofspecificrecommen-dationsaroundtheworld,basedoneconomicandeduca-tionaldifferences.For instance, the routineevaluationofthyroid nodules may not necessitate ultrasonography insomecountriesthatcannotaffordthewidespreadpurchaseofultrasoundequipmentorinwhichthereisashortageofexperiencedthyroidultrasonographers. Transparencyforthis4-stepmethodologywillbere-alized bymaintaining a record of theCPGdevelopmentprocess.Aron andPogach (47) reviewed the importanceof transparencyas applied to thedivergentEBMrecom-mendationsfortargethemoglobinA1clevelsindiabetes.


Unfortunately, transparency is confounded by seman-tic imprecisionand is acommonshortcomingamongallprotocols inTable 2. In otherwords, human language isstill relatively imprecise when technical concepts, hu-man subjectivities, and vague or ambiguous terms arebeingdescribed.Accordingly,despite thebest intentions,the concept of full transparency is untenable. The 2010AACEprotocoladdressessemanticimprecisionby(1)us-ingacontrolledmedicalvocabulary in the recommenda-tionphraseologyforeasyadaptationintocomputer-inter-pretableguidelines (CIG) (48-51)and (2) includingboth

numerical and semantic descriptors of clinical evidence.The key procedural steps for the 2004 and 2010AACEprotocolmethodologiesaresummarizedandcomparedinTable7.

Review Process Themultilevel review process requires iterations ofreviewbythechairpersonandprimarywritersaftereachrevisionbyassigned“reviewers,”theAACEPublicationsCommittee,theAACEBoardofDirectors,and,finally,theeditorialprocessofEndocrine Practice.Specialreviewers

Table 32010 American Association of Clinical Endocrinologists Protocol for

Production of Clinical Practice Guidelines—Step I: Evidence Ratinga

Numerical descriptor Semantic descriptor (evidence level) (reference methodology)

1 Meta-analysisofrandomizedcontrolledtrials(MRCT) 1 Randomizedcontrolledtrial(RCT) 2 Meta-analysisofnonrandomizedprospectiveorcase-controlledtrials(MNRCT) 2 Nonrandomizedcontrolledtrial(NRCT) 2 Prospectivecohortstudy(PCS) 2 Retrospectivecase-controlstudy(RCCS) 3 Cross-sectionalstudy(CSS) 3 Surveillancestudy(registries,surveys,epidemiologicstudy)(SS) 3 Consecutivecaseseries(CCS) 3 Singlecasereports(SCR) 4 Noevidence(theory,opinion,consensus,orreview)(NE) a1=strongevidence;2=intermediateevidence;3=weakevidence;4=noevidence.

Table 42010 American Association of Clinical Endocrinologists Protocol

for Production of Clinical Practice Guidelines—Step II:Evidence Analysis and Subjective Factors

Study design Data analysis Interpretation of results

Premisecorrectness Intent-to-treat Generalizability Allocationconcealment(randomization) Appropriatestatistics Logical Selectionbias Incompleteness Appropriateblinding Validity Usingsurrogateendpoints(especiallyin “first-in-its-class”intervention) Samplesize(betaerror) NullhypothesisversusBayesianstatistics


(non-AACEmembers)maybeinvitedtoparticipateinthereviewprocess.Allauthorsandreviewerswillbeselectedon the basis of expert credentials covering the topic (ortopics)ofinterest,absenceofanymultiplicityofintereststhat would compromise the usefulness of the CPG, andcommitment to complete their assignments according tothestatedtimeline.Thisreviewprocesswillbeexpeditedby selecting topics that are amenable to an abbreviated(6-month)timeline.Thiscanbeaccomplishedbyfocusingonmorespecific topicsandbyusingaquestion-orientedapproachandtheory-drivenliteraturesearch.

Implementation ImplementationofCPGadherentwiththe2010AACEprotocolwillincludethefollowingfactors:

1. Developmentofcontinuingmedicaleducationcred-it linked to the readingofandcorrect responses toquestionsonthecontentoftheCPG

Table 52010 American Association of Clinical Endocrinologists Protocol

for Production of Clinical Practice Guidelines—Step III:Grading of Recommendations; how Different Evidence levels Can Be Mapped

to the Same Recommendation Gradea

Best Subjective evidence factor Two-thirds Recommendation level impact consensus Mapping grade

1 None Yes Direct A 2 Positive Yes Adjustup A

2 None Yes Direct B 1 Negative Yes Adjustdown B 3 Positive Yes Adjustup B

3 None Yes Direct C 2 Negative Yes Adjustdown C 4 Positive Yes Adjustup C

4 None Yes Direct D 3 Negative Yes Adjustdown D

1,2,3,4 NA No Adjustdown D

aStartingwiththeleftcolumn,bestevidencelevels(BEL),subjectivefactors,andconsensusmapto recommendationgradesintherightcolumn.Whensubjectivefactorshavelittleornoimpact(“none”), thentheBELisdirectlymappedtorecommendationgrades.Whensubjectivefactorshaveastrongimpact, thenrecommendationgradesmaybeadjustedup(“positive”impact)ordown(“negative”impact).Ifatwo- thirdsconsensuscannotbereached,thentherecommendationgradeisD.NA=notapplicable(regardless ofthepresenceorabsenceofstrongsubjectivefactors,theabsenceofatwo-thirdsconsensusmandatesa recommendationgradeD).

Table 62010 American Association

of Clinical Endocrinologists Protocol forProduction of Clinical Practice Guidelines—Step IV:

Examples of Qualifiers That May BeAppended to Recommendations

Cost-effectiveness Risk-benefitanalysis Evidencegaps Alternativephysicianpreferences(dissentingopinions) Alternativerecommendations(“cascades”) Resourceavailability Culturalfactors Relevance(patient-orientedevidencethatmatters)


Table 7Comparisons Between the 2004 and 2010

American Association of Clinical Endocrinologists (AACE)Clinical Practice Guidelines (CPG) Protocol Methodologiesa

Procedural step 2004 AACE CPG protocol 2010 AACE CPG protocol

Mandate(topic) NewCPG:AACEBOD Sameapprovalprocessas2004 Updates:AACECPGsubcommitteerequires Topicconstrainedtoclinicalquestionorproblem BODapproval

Appointmentoftaskforce NewCPG:AACEBOD Sameapprovalprocessas2004 chairperson Updates:samechairreappointedbyAACE Chairpersonexplicitlycommitstotaskandtimeline CPGsubcommitteerequiresBODapproval ChairpersoncompletesCPGtraining

Selectionoftaskforcemembers NewCPG:taskforcechair Sameapprovalprocessas2004 (primarywriters) Updates:taskforcechair Taskforcemembersexplicitlycommittotask/timeline Both:requireCPGsubcommitteechair andcompleteCPGtraining approval

Selectionofcosponsoringand/or Nominatedbytaskforcechairperson Sameapprovalprocessas2004 endorsingsocieties RequiresBODapproval

Primaryliteraturesearch Byprimarywriters ByprimarywriterswithassistancebyAACEstaff; willbeguidedbymiddle-rangetheoriestoaccount forcomplexinteractionsinpatientmanagement

StepI(seeTable3) PaperscitedinAppendixtextandin PaperscitedinAppendixtextandinreference referencesectionappendedby[EL1], sectionappendedbynumericalandsemantic [EL2],[EL3],or[EL4] descriptors:forexample,[EL1;RCT],[EL2;PCS], [EL3;SCR],or[EL4;NE]

StepII(seeTable4) Nocommentsbasedonstudyflaws Subjectivefactorsareprovidedasannotationsin referencesectionandmayalsobediscussedin Appendix:forexample,[EL1;RCT;smallsample size(N=12)withselectionbiasandnot generalizabletopatients>65yearsold]

StepIII(seeTable5) GradeandBELappendedtorecommendation Recommendationphraseologytocreateclinical inExecutiveSummary:forexample,(Grade algorithm B;BEL2[nonrandomized]) Grade,levelofconsensus,andBELappendedto ExecutiveSummary:forexample,(GradeB [unanimousconsensus];BEL2;NRCT) Optionalalternativerecommendation(“cascade”) maybeprovided:forexample,(GradeB [unanimousconsensus];BEL2;NRCT;this recommendationmaynotapplywherethyroid ultrasonographyisnotavailable)

StepIV(seeTable6) Additionalqualifiersnotgiven Additionalqualifiersarepartofannotationin referencesectionandmayalsobediscussedin Appendix:forexample,[RCT;EL1;smallsample size(N=12)withselectionbiasandnot generalizable;studyisrelevantbutinterventionis costly;cost-effectivenessanalysisnotreported]

Reviewprocess Multilevel:chair,primarywriters,reviewers, Multilevel:chair,primarywriters,reviewers,special specialreviewer(ifneeded),publications reviewer(ifneeded),publicationscommittee,BOD, committee,BOD,peerreviewbyEndocrine peerreviewbyEndocrine Practice Practice

CMEcredit None LinkedtoCPG

Readersurveys None UsedforCPGupdates

Electronicimplementation None Clinicalknowledgemanagementsystemintegrated withEMRandotherhealthcareinformationsystems

a BEL=bestevidencelevel;BOD=BoardofDirectors;CME=continuingmedicaleducation;EL=evidencelevel;EMR=electronicmedical records.Forotherabbreviations,seetextabbreviationboxandTable3.


2. Distribution of surveys to AACE membership re-gardingtherelevanceandutilityoftheCPGandthenincorporationofresponsesintoCPGupdates

3. Developmentofelectronicimplementationofclini-cal knowledge management systems that are evi-dence-based and can be integrated with electronicmedical records and other health care informationsystems

CONClUSION

AACEiscommittedtoenhancingtheabilityofclini-calendocrinologiststoprovidethehighestqualityofmedi-calcareandimprovepublichealth.InfulfillingthisAACEmission,CPGcanbeinvaluableassets.Themetamorpho-sisofCPGfrominformal,biased,opinionpapersandcon-sensusreportsintoformalizedEBMdocumentsmaynowevolvefurther.Movingforward,AACECPGwillbeuser-friendlierandmoretransparentlydeveloped.Theywillhy-bridizehardevidence,softexperience-basedimpressions,andpragmaticimplementationtoolsfortheelectronicageof medicine. Ultimately, the target is a clinical decisionsupportsystem(52)emphasizing“informedjudgment,”inwhichscience,beliefs,andcomputerizationareeachnec-essary,butnotsufficient,components.Examplesinclude,but are not limited to, CIG (53), “neuro-fuzzy systems”(54),andBayesiannetworks(55).

DISClOSURE

Chairperson and Primary Writer: Dr. Jeffrey I. Mechanick reports that he has re-ceived speaker honoraria from Abbott Nutrition andsanofi-aventisU.S.LLC.

Primary Writers: Dr. Pauline M. Camacho reports that she has re-ceived research grant support for her role as principalinvestigator from the Alliance for Better Bone Health(Procter&Gambleandsanofi-aventisU.S.LLC),EliLillyandCompany,andNovartisAG. Dr. Rhoda h. Cobin reports that she has receivedspeakerandadvisorypanelhonorariafromBristol-MyersSquibbandNovoNordisk,Inc. Dr. Alan J. Garber reports that he has receivedspeaker honoraria from GlaxoSmithKline plc, Merck &Co., Inc., Novo Nordisk Inc., and Daiichi Sankyo, Inc.,consultant honoraria from GlaxoSmithKline plc, Merck&Co., Inc.,NovoNordisk Inc., andRocheDiagnostics,and research grant support from Bristol-Myers Squibb,GlaxoSmithKline plc, Metabasis, Novo Nordisk Inc.,Merck&Co., Inc., sanofi-aventisU.S. LLC, andRocheDiagnostics. Dr. Jeffrey R. Garber reports that he has receivedspeaker honoraria from Abbott Laboratories, consultant

feesfromKingPharmaceuticals®,Inc.,andresearchgrantsupportfromGenzymeCorporation. Dr. hossein Gharib reports that he does not haveany relevantfinancial relationshipswith any commercialinterests. Dr. Steven M. Petak reports that he has receivedspeaker honoraria from Amgen Inc., Novartis AG, andsanofi-aventisU.S.LLC. Dr. helena W. RodbardreportsthatshehasreceivedadvisoryboardhonorariafromAstraZeneca,Biodel,Inc.,GlaxoSmithKlineplc,andMannkindCorporation,speakerhonorariafromAstraZeneca,Bristol-MyersSquibb,Merck&Co.,Inc.,andNovoNordiskInc.,andclinicalresearchgrant support fromBiodel, Inc.,NovoNordisk Inc., andsanofi-aventisU.S.LLCandthatherspousehasreceivedconsultant fees fromDexComTM and sanofi-aventisU.S.LLC. Dr. Dace l. Trencereportsthatshehasreceivedre-searchgrantsupportforherroleasprincipalinvestigatorfromBayerAGandisastockholderofsanofi-aventisU.S.LLCandMedtronic,Inc.

Special Reviewers: Dr. Mor Pelegreportsthatshedoesnothaveanyrele-vantfinancialrelationshipswithanycommercialinterests. Dr. Wael haddara reports that he does not haveany relevantfinancial relationshipswith any commercialinterests.

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APPENDIx: GlOSSARY OF TERMS

Allocation concealment.Preventionofthenextassignmentinaclinicaltrialfrombeingknown;necessaryforrandomization.

Bayesian network.Adecision-theoreticmodelthatcanexpressconditionaldependenciesinamannerthatisbothacces-sibletohumansandcomprehensibletocomputers.AccessibilitytohumansreferstoavailabilityovertheInternet,orothercomputer-basedsystem,andinalanguagethatisunderstandable.

Bayesian statistics.Methodinwhichnewassumptionsaboutparametersarecontinuallyrevisedonthebasisofnewsam-pledataandasynthesisofinformationaboutpreviousassumptions(“priordistribution”).“Degreesofbelief”orlevelsofcertainty—whicharesubjecttochangeasmoreevidenceemerges—thatahypothesisiscorrectareusedinsteadofnumeri-calfrequencies,whichareusedinnon-Bayesianstatistics.TheuseofBayesianstatisticsisimportantduringevaluation,forexample,oftheprobabilitythatapositivetestresultisafalsepositive,whichiscriticallyimportantindeterminingtheutilityofadiagnostictestforararedisease.

Beta error.Aformofstatisticalerror(“ofthesecondkind”ortypeII)—concludingthatsomethingisnegativewhenitac-tuallyispositive(a“falsenegative”).Betaerrorisafunctionofsamplesize,amongothervariables.

Blinding.Insingle-blindclinicalstudies,thestudysubjectsarenotawareofthetreatmenttheyarereceiving.Indouble-blindclinicalstudies,theresearchersandthesubjectsareunawareofwhichtreatmentisallocatedtowhom.Blindingisusedtopreventbiasinclinicalresearch.

Clinical algorithm.Astep-by-stepprocedureforsolvingaclinicalproblemwithuseofconditional“if/then”logicstatements.

Clinical decision-support systems.Systemsthataidcliniciansingatheringrelevantdata,makingclinicaldecisions,andmanagingmedicalactionsmoreeffectively.

Clinical knowledge management systems.Systemsthathelphealthcareorganizationsusepracticesthat,throughmoreeffectiveutilizationoftheirknowledgeassets,increasethecompetitiveadvantageofanorganizationinahighlydynamicenvironment.Suchsystemsareapplicableinasettingwheremedicalknowledgechangesrapidlyandwherehealthcareprovidersandpatientsinteractindistributedandcollaborativeprocesses.Distributedprocessesrefertoanetworkofco-ordinatedcentersthatprovidecomplementaryservicesindifferentlocations—rangingfromthehighlycomplexsuchasreferralhospitalstothelesscomplexsuchassolopractices.

Clinical practice guidelines (CPG).Systematicallydevelopeddocumentsthatassistpractitionersmakeappropriatehealthcaredecisionsforspecificclinicalproblems.

Computer-interpretable guidelines (CIG).Aguidelinerepresentationthatisaccessibletohumansandsupportscomput-er-basedexecutionthatrequiresautomaticinference.CIGscandeliverpatient-specificknowledgeatthepointofcaredur-ingclinicalencounters.

Controlled medical vocabulary.Alistoftermidentifiersthatdisambiguatewordsusedinclinicalpracticeandthemedi-calliterature.

Evidence-based medicine (EBM).Alearningstrategy.Thedeliberateuseofclinicalevidenceinthecareofindividualpatientsandcomposedof4parts:formulatingaclinicalquestionfromapatient’sproblem,searchingthemedicalliteratureforrelevantclinicalpublications,criticallyappraisingtheevidenceforvalidityandusefulness,andimplementingusefulfindingsinclinicalpractice.

Intent-to-treat.Pertainingtoclinicaltrials:basedontheinitialtreatmentallocationandnotthetreatmentthatwaseventu-allyadministered.


Medical humanism.Relationshipbetweencaregiverandpatientthatiscompassionate,empathetic,andsensitivetopa-tientvalues,autonomy,andethnoculturalbackground.

Middle-range theory.Theoriesorganizefactsorobservationsintoastructurallycoherentsystemthatcanultimatelyex-plainreality.Amiddle-rangetheoryliesbetweendetaileddescriptionsandgeneralizedmodels.

Neuro-fuzzy system.Combininghumanlikereasoningwithartificialneuralnetworks;aformofartificialintelligence.

Non-Bayesian statistical analysis.Methodinwhichprobabilitiesareexpressedintermsofnumericalfrequencies.Thisistheconventionalmethodusedinclinicalstudies.

Nonparametric.Statisticalteststhatarenotbasedonanyassumption,suchasanormaldistributionofdata.Theyarealsoknownasdistribution-freetests,andthedataaregenerallyrankedorgrouped.

Null hypothesis.Thestatisticalhypothesisthatpredictsthatthereisnodifferenceorrelationshipamongthevariablesstudiedthatcouldnothaveoccurredbychancealone.

Patient-oriented evidence that matters (POEMs).Evidencethatdirectlyinformscliniciansaboutproceduresthathelppatientslivelongerandbetter.

Process flow.Asappliedtoactualclinicalencounters,thereal-lifesequenceofdata-gathering,decisionmaking,andactions.

Scientific substantiation.Evidencearisingfromwell-designedclinicalstudieswithuseofthescientificmethod:induc-tiontocreateamodel,deductionofatestablehypothesis,observationandexperimentationtogatherdata,reasoningtorevisetheinitialmodel,andthenrepeatingtheprocess.EBMattemptstocategorizeclinicalevidenceintermsof“levels”ofscientificsubstantiation,fromweaktointermediatetostrong.

Semantic imprecision.Inabilityoflanguagetodescribeaphenomenon,suchaslevelsofscientificsubstantiation,inare-produciblewayforallreadersofadocument.Vaguenessandambiguityareformsofsemanticimprecision.

Systems biology.Aninterdisciplinaryapproachthatfocusesoncomplexinteractions,aimstodiscoveremergentproper-ties,andeventuallyleadstounderstandingtheentiretyofabiologicprocess.

Technical review.Processinwhichclinicalpublicationsareratedonthebasisoftheirlevelsofscientificsubstantiation(levelsofevidence).

Transparency.MannerinwhichthecomplicatedprocessofproducingCPGisexplicitlydescribed,writtenforeasycom-prehension,andmadeaccessible.Thispertainstothetechnicalreviewoftheevidence,incorporationofsubjectivefactors,reportingoflevelsofconsensus,andassignmentofthefinalrecommendationgrade.

aace guidelines american association of clinical endocrinologists

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