How GRADE could help to implement the evidence

How GRADE could help to implement the evidence
Holger Schünemann, MD, PhD Professor and Chair, Dept. of Clinical Epidemiology & Biostatistics Professor of Medicine Michael Gent Chair in Healthcare Research McMaster University, Hamilton, Canada How GRADE could help to implement the evidence

Content Systematic Reviews & GRADE Evidence & judgments
Pulmonary rehabilitation compared to usual community care for COPD with recent exacerbation Bibliography: Puhan M, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2010, Issue 11. Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects Risk with Usual community care Risk difference with Pulmonary rehabilitation (95% CI) Hospital admission 250 (6 studies) 3-18 months ⊕⊕⊕⊕ HIGH OR (0.08 to 0.58) 405 per 1000 275 fewer per 1000 (from 122 fewer to 353 fewer) Mortality 110 (3 studies) 3-48 months ⊕⊕⊕⊝ MODERATE2 due to imprecision OR (0.1 to 0.84) Low1 100 per 1000 70 fewer per 1000 (from 15 fewer to 89 fewer) High1 500 per 1000 281 fewer per 1000 (from 43 fewer to 409 fewer) Quality of life (CRQ) dyspnea Chronic Respiratory Questionnaire3. Scale from: 1 to 7. 258 (5 studies) 12 and 76 weeks ⊕⊕⊕⊝ MODERATE4 due to imprecision The mean quality of life (sgrq) total in the control groups was 3.1 The mean quality of life (crq) dyspnea in the intervention groups was 0.97 higher (0.35 to 1.58 higher) Quality of life (SGRQ) total St George's Respiratory Questionnaire5. Scale from: 0 to 100. 127 (3 studies) 12 and 26 weeks The mean quality of life (sgrq) total in the control groups was 50 The mean quality of life (sgrq) total in the intervention groups was 9.88 lower (5.37 to 14.4 lower) Ambulation (as measured by 6 min walking distance) distance in meters6 299 (6 studies) weeks7 ⊕⊕⊕⊝ MODERATE4,8 due to imprecision The mean ambulation (as measured by 6 min walking distance) in the intervention groups was 77.7 higher (12.21 to higher) Resource use - not reported - See footnote Systematic Reviews & GRADE Evidence & judgments Recommendation, health policy & implementation

Systematic Reviews & GRADE
Content Examples and summary from leading/co-leading 15 guideline projects 11 World Health Organization World Allergy Organization, Allergic Rhinitis in Asthma, American Thoracic Society (2) Pulmonary rehabilitation compared to usual community care for COPD with recent exacerbation Bibliography: Puhan M, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2010, Issue 11. Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects Risk with Usual community care Risk difference with Pulmonary rehabilitation (95% CI) Hospital admission 250 (6 studies) 3-18 months ⊕⊕⊕⊕ HIGH OR (0.08 to 0.58) 405 per 1000 275 fewer per 1000 (from 122 fewer to 353 fewer) Mortality 110 (3 studies) 3-48 months ⊕⊕⊕⊝ MODERATE2 due to imprecision OR (0.1 to 0.84) Low1 100 per 1000 70 fewer per 1000 (from 15 fewer to 89 fewer) High1 500 per 1000 281 fewer per 1000 (from 43 fewer to 409 fewer) Quality of life (CRQ) dyspnea Chronic Respiratory Questionnaire3. Scale from: 1 to 7. 258 (5 studies) 12 and 76 weeks ⊕⊕⊕⊝ MODERATE4 due to imprecision The mean quality of life (sgrq) total in the control groups was 3.1 The mean quality of life (crq) dyspnea in the intervention groups was 0.97 higher (0.35 to 1.58 higher) Quality of life (SGRQ) total St George's Respiratory Questionnaire5. Scale from: 0 to 100. 127 (3 studies) 12 and 26 weeks The mean quality of life (sgrq) total in the control groups was 50 The mean quality of life (sgrq) total in the intervention groups was 9.88 lower (5.37 to 14.4 lower) Ambulation (as measured by 6 min walking distance) distance in meters6 299 (6 studies) weeks7 ⊕⊕⊕⊝ MODERATE4,8 due to imprecision The mean ambulation (as measured by 6 min walking distance) in the intervention groups was 77.7 higher (12.21 to higher) Resource use - not reported - See footnote Systematic Reviews & GRADE Evidence & judgments Recommendation, health policy & implementation

Background WHO develops advice (recommendations) “all the time”
Format differs, methods differ, much criticism May 2005 World Health Assembly resolution WHO Director-General "to undertake an assessment of WHO's internal resources, expertise and activities in the area of health research, with a view to developing a position paper on WHO's role and responsibilities in the area of health research, and to report through the Executive Board to the next World Health Assembly."

Guideline development Process

Panel P I C O Systematic review evidence profile with GRADEpro Create
Summary of findings & estimate of effect for each outcome Outcomes across studies Rate quality of evidence for each outcome Formulate question Randomization increases initial quality Select outcomes Rate importance Risk of bias Inconsistency Indirectness Imprecision Publication bias P I C O Outcome Critical Grade overall quality of evidence across outcomes based on lowest quality of critical outcomes High Outcome Critical Moderate Grade down Low Outcome Important Very low Outcome Not important Large effect Dose response Confounders Grade up Panel Guideline development Formulate recommendations: For or against (direction) Strong or conditional/weak (strength) By considering: Quality of evidence Balance benefits/harms Values and preferences Revise if necessary by considering: Resource use (cost) “We recommend using…” “We suggest using…” “We recommend against using…” “We suggest against using…”

Outcome generation and selection
Multidisciplinary panels Researchers, epidemiologists, public health officers, methodologists, patient representatives… Delphi process 3 rounds List of possible outcomes from literature Panel members review and add List of all outcomes grouped by theme Panel members rate importance Final agreement and results

Outcomes for screening on a scale of 1 (not important) to 9 (critical)
Mortality from cervical cancer 8.2 Cervical cancer Incidence 8.3 Detected CIN 2,3 7. 9 Major Infections (requiring hospital admission and antibiotics, e.g. PID) 6.0 Maternal bleeding 5.8 Premature delivery 5.7 Fertility 5.4 Identification of STIs (benefit) 5.0 Minor infections (requiring outpatient treatment only) 3.8

Challenges and advantages of this approach
Often starting with many outcomes Experts initially focused on what they know from research studies Requires detailed explanations ↓ Participation of panel members Perspective taken Complete Everyone involved Independent ratings Numerical estimates Well documented and kept record Transparent Reduces work

WHO influenza guidelines
New guideline on pharmacological management of influenza Previously few randomized trials Low quality evidence for many outcomes (imprecision) Industry sponsored – publication bias Not all outcomes Review of observational studies To inform guidelines

Methods Standard systematic review 10 PICO → recommendations approach
MEDLINE, EMBASE, CENTRAL, CINAHL, SIGLE, the Chinese Biomedical Literature Database, Panteleimon and LILACS for relevant studies up to November 2010 contacted pharmaceutical companies and international agencies RevMan 5.1 10 PICO → recommendations approach Outcomes determined through Delphi process previously QoE according to GRADE approach GRADEpro ( Risk of bias using modified Ottawa Newcastle scale

Results Question: Should oseltamivir vs. no antiviral treatment be used for influenza (follow-up: 30 days)? Quality assessment Summary of Findings Participants (studies) Risk of bias Inconsistency Indirectness Imprecision Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects With no antiviral treatment With oseltamivir Risk with no antiviral treatment Absolute effect with Oseltamivir (95% CI) Mortality 681 (3 studies) no serious risk of bias no serious inconsistency no serious indirectness no serious imprecision undetected1 ⊕⊕⊝⊝ LOW1 59/242 (24.4%) 31/439 (7.1%) adj OR (0.13 to 0.43) 240 deaths per 1000 172 fewer deaths per 1000 (from 120 to 201 fewer) 1557 (9 studies) serious2 ⊕⊝⊝⊝ VERY LOW1,2 due to risk of bias 61/320 (19.1%) 228/1237 (18.4%) OR (0.23 to 1.14)3 101 fewer deaths per 1000 (from 172 fewer to 25 more) Hospitalisation (5 studies) undetected4 ⊕⊕⊝⊝ LOW4 1238/ (1.2%) 431/50125 (0.86%) adj OR (0.66 to 0.89) 12 hospitalisations per 1000 3 fewer hospitalisations per 1000 (from 1 to 4 fewer) (6 studies) ⊕⊝⊝⊝ VERY LOW2,4 due to risk of bias 1738/ (1.2%) 1086/96352 (1.1%) OR (0.66 to 0.86) 3 fewer hospitalisations per 1000 (from 2 to 4 fewer) ICU admissions/mechanical ventilation/respiratory failure 1032 (6 studies5) Serious5 serious6 ⊕⊝⊝⊝ VERY LOW1,6 due to risk of bias, inconsistency - 200/1032 (19.4%) Complications - Pneumonia (3 studies) ⊕⊝⊝⊝ VERY LOW4,6 due to inconsistency 2111/ (2.1%) 647/50017 (1.3%) adj OR (0.59 to 1.16) 21 pneumonias per 1000 4 fewer pneumonias per 1000 (from 9 fewer to 3 more) (6 studies) ⊕⊝⊝⊝ VERY LOW2,4,6 due to risk of bias, inconsistency 3244/ 166256 (2%) 1273/99020 (1.3%) OR (0.46 to 0.88) 20 pneumonias per 1000 7 fewer pneumonias per 1000 (from 2 to 10 fewer)

Content Systematic and transparent approach
Transparently lay out rationale for recommendations Manage COI Pulmonary rehabilitation compared to usual community care for COPD with recent exacerbation Bibliography: Puhan M, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2010, Issue 11. Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects Risk with Usual community care Risk difference with Pulmonary rehabilitation (95% CI) Hospital admission 250 (6 studies) 3-18 months ⊕⊕⊕⊕ HIGH OR (0.08 to 0.58) 405 per 1000 275 fewer per 1000 (from 122 fewer to 353 fewer) Mortality 110 (3 studies) 3-48 months ⊕⊕⊕⊝ MODERATE2 due to imprecision OR (0.1 to 0.84) Low1 100 per 1000 70 fewer per 1000 (from 15 fewer to 89 fewer) High1 500 per 1000 281 fewer per 1000 (from 43 fewer to 409 fewer) Quality of life (CRQ) dyspnea Chronic Respiratory Questionnaire3. Scale from: 1 to 7. 258 (5 studies) 12 and 76 weeks ⊕⊕⊕⊝ MODERATE4 due to imprecision The mean quality of life (sgrq) total in the control groups was 3.1 The mean quality of life (crq) dyspnea in the intervention groups was 0.97 higher (0.35 to 1.58 higher) Quality of life (SGRQ) total St George's Respiratory Questionnaire5. Scale from: 0 to 100. 127 (3 studies) 12 and 26 weeks The mean quality of life (sgrq) total in the control groups was 50 The mean quality of life (sgrq) total in the intervention groups was 9.88 lower (5.37 to 14.4 lower) Ambulation (as measured by 6 min walking distance) distance in meters6 299 (6 studies) weeks7 ⊕⊕⊕⊝ MODERATE4,8 due to imprecision The mean ambulation (as measured by 6 min walking distance) in the intervention groups was 77.7 higher (12.21 to higher) Resource use - not reported - See footnote Systematic Reviews & GRADE Evidence & judgments Recommendation, health policy & implementation

Judgments/explanations
1 Although we did not downgrade, publication bias cannot be excluded and is of concern. 2 Studies not adjusted for potential confounding factors. 3 Significant differences in effect for pandemic versus seasonal influenza (see subgroup analyses table). 4 Publication bias a concern since large studies had for-profit funding and weighted heavily in analyses. 5 No independent comparison group. 6 High heterogeneity among studies. 7 Measured in select patients in trials.

Summary of evidence by outcome
Evidence Profiles Summary of Findings Tables Includes all critical outcomes And important outcomes if less than 7 together No outcomes that are not important Estimates of effects and confidence in these estimates (graded)

Getting from evidence to recommendations - GRADE
Recommendations are based on judgments: Quality of evidence (confidence in estimates of effect) Balance between benefits and downsides Values and preferences Resource use But judgments need to be based on the best available evidence and transparent

Strength of recommendation
“The strength of a recommendation reflects the extent to which we can, across the range of patients for whom the recommendations are intended, be confident that desirable effects of a management strategy outweigh undesirable effects.” Strong or weak/conditional

Balancing desirable and undesirable consequences
↑ Allergic reactions ↑ Local skin reactions ↑ Nausea ↑ Resources ↑ QoL ↓ Death ↓ Morbidity ↑ herd immunity Conditional Strong For Against

Recommendations, health policy & implementation
Content Pulmonary rehabilitation compared to usual community care for COPD with recent exacerbation Bibliography: Puhan M, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2010, Issue 11. Outcomes No of Participants (studies) Follow up Quality of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects Risk with Usual community care Risk difference with Pulmonary rehabilitation (95% CI) Hospital admission 250 (6 studies) 3-18 months ⊕⊕⊕⊕ HIGH OR (0.08 to 0.58) 405 per 1000 275 fewer per 1000 (from 122 fewer to 353 fewer) Mortality 110 (3 studies) 3-48 months ⊕⊕⊕⊝ MODERATE2 due to imprecision OR (0.1 to 0.84) Low1 100 per 1000 70 fewer per 1000 (from 15 fewer to 89 fewer) High1 500 per 1000 281 fewer per 1000 (from 43 fewer to 409 fewer) Quality of life (CRQ) dyspnea Chronic Respiratory Questionnaire3. Scale from: 1 to 7. 258 (5 studies) 12 and 76 weeks ⊕⊕⊕⊝ MODERATE4 due to imprecision The mean quality of life (sgrq) total in the control groups was 3.1 The mean quality of life (crq) dyspnea in the intervention groups was 0.97 higher (0.35 to 1.58 higher) Quality of life (SGRQ) total St George's Respiratory Questionnaire5. Scale from: 0 to 100. 127 (3 studies) 12 and 26 weeks The mean quality of life (sgrq) total in the control groups was 50 The mean quality of life (sgrq) total in the intervention groups was 9.88 lower (5.37 to 14.4 lower) Ambulation (as measured by 6 min walking distance) distance in meters6 299 (6 studies) weeks7 ⊕⊕⊕⊝ MODERATE4,8 due to imprecision The mean ambulation (as measured by 6 min walking distance) in the intervention groups was 77.7 higher (12.21 to higher) Resource use - not reported - See footnote Systematic Reviews & GRADE Evidence & judgments Recommendations, health policy & implementation

Depending on contact investigation strategy used, resource utilization and implications will vary.
Opportunity cost may be high. Feasibility is dependent on existing and well functioning programs. Resources worth in smear positive index cases

Absolute effect at 1 year
Should cryotherapy versus LEEP be used in women with histologically confirmed cervical intraepithelial neoplasia? Quality assessment No of patients Effect Quality Importance No. of studies Design Limitations Inconsistency Indirectness Imprecision Other Cryotherapy LEEP Relative (95% CI) Absolute effect at 1 year (95% CI) Recurrence CIN2–3 (follow-up 12 months randomized trials; 3–85 months observational studies) 1 randomized trials no serious limitations no serious inconsistency no serious indirectness seriousa,b none 12/161 (7.5%) 4/168 (2.4%) OR 3.3 (1.04 to 10.46) 51 more per 1000 (from 1 to 179 more) O CRITICAL 3 observational studies no serious imprecision 2227/14 387 (15.5%) 319/7454 (4.3%) OR (1.89 to 3.75) — OO 2.4%c 37 more per 1000 (from 20 to 60 more) Cervical cancer (follow-up 12 months randomized trials; 3–85 months to 26 years observational studies) very seriousa 0/200 (0%) 0 fewer per 1000d 2 2/679 (0.3%) 3/3350 (0.1%) 0 fewer per 1000e Treatment unacceptable to women (follow-up 2 weeks; acceptability question) very seriousf 15/170 (8.8%) 8/186 (4.3%) OR (0.89 to 5.22) 45 more per 1000 (from 5 fewer to 147 more) All severe adverse events (follow-up mean 12–16 months; stenosis and PID) 3/300 (1%) 2/298f (0.67%) 0.4 more per 1000 (from 8 fewer to 9 more) All severe adverse events (follow-up 33 months; PID, plug syndrome, stenosis, blood transfusion) 5 randomized trials serioush 136 480 OR 0.53 (0.1 to 2.88) 4%i 18 fewer per 1000 (from 36 fewer to 67 more) All severe adverse events (follow-up 12 months; PID, stenosis, major bleeding) 9 observational studies serious limitationsj seriousi seriousf 1/2233 38/960 (4%)a 10 fewer per 1000 (from 20 fewer to 0) OOO

Recommendation In settings where LEEP is available and accessible, and women present with CIN lesions extending into the cervical canal, the expert panel suggests treatment with LEEP over cryotherapy (conditional recommendation, OO quality evidence) Remarks: The benefits of LEEP were greater than those of cryotherapy, and the harms were fewer in these women. However, since there are greater resource implications for LEEP than cryotherapy, and thus LEEP is not available in all settings, a conditional recommendation was made.

Implications of a conditional/weak recommendation
Patients: The majority of people in this situation would want the recommended course of action, but many would not Clinicians: Be more prepared to help patients to make a decision that is consistent with their own values/decision aids and shared decision making Policy makers: There is a need for substantial debate and involvement of stakeholders

Implications of a strong recommendation
Patients: Most people in this situation would want the recommended course of action and only a small proportion would not Clinicians: Most patients should receive the recommended course of action Policy makers: The recommendation can be adapted as a policy in most situations , can be used as quality indicator/performance measure

Only two of six performance measures seemed reasonable

WHO evaluation & feedback
WHO staff & guideline review committee members (GRC) invited to feedback (Jan 2011) about using GRADE approach what worked what did not work Group discussion (NGT),

Summary of feedback Transparency of the GRADE process helps
Requirement for a good Chair methods knowhow to move the process For observational studies we need better/ ¿different? summaries (e.g. narrative versions) Integration and elicitation of values and preferences was frequently challenging For global guidelines: issues around the description of baseline risks and applicability across countries require work

Summary of feedback Variability in baseline risk → weak or conditional recommendations should follow A description of the modifying factors and the layout of the evidence could be a great benefit and will facilitate implementation Measures should be taken to streamline the timing of the development of guidelines Working with centers, training, and capacity building of these centers who collaborate with WHO a priority for implementing GRADE Impact evaluation (of current process for development of guidelines) should take place

Conclusions (WHO) guidelines should be based on the best available evidence to be evidence based GRADE not avoid judgments but provides framework combines what is known in health research methodology and provides an approach to improve communication GRADE process works – is it better? Change in culture towards the use of evidence Transparency in decision making and judgments is key

Thanks Nancy Santesso, Andy Oxman, Suzanne Hill
WHO staff who participated in providing feedback

Results - PRISMA Additional records identified through other sources
Studies awaiting assessment (n = 6) Studies awaiting translation (1) Papers could not obtain in full (5) Records identified through database searching (all study designs) EMBASE, MEDLINE = 9873 SIGLE = 7 CINAHL = 1062 LILACS = 19 COCHRANE = 301 Chinese Biomedical Literature Database = 914 Panteleimon = 12 (Total n = 12176) Additional records identified through other sources Pharmaceutical companies (n = 12) Reference lists of relevant papers (n=15) Records after duplicates removed (n = 7456) Records screened (n = 7483) Records excluded (n = 6563) Full-text articles assessed for eligibility (n = 920 ) Full-text articles excluded (n = 825) Excluded for Not influenza or influenza like illness Fewer than 25 people Randomised controlled trial, or not an observational study Not antiviral agent Antiviral agents analysed together Prophylaxis No outcomes reported Studies included N = 89 Question studies 7 studies 6 studies 0 studies 8 16 1 study 2 studies Note: one study may be relevant to multiple questions

Results Should oseltamivir versus no treatment be used to treat influenza? Mortality (adjusted) Mortality (unadjusted)

Recommendation The Guidelines Group recommends that TB programs/clinicians use/do not use fluoroquinolones in the treatment of all patients with MDR (Strong (conditional) recommendation/ low (very low, low, moderate, high) grade of evidence)

Example: Oseltamivir for Avian Flu
Recommendation: In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence). Remarks: This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places relatively low values on adverse reactions, the development of resistance and costs of treatment. Schunemann et al. The Lancet ID, 2007

Other explanations Remarks: Despite the lack of controlled treatment data for H5N1, this is a strong recommendation, in part, because there is a lack of known effective alternative pharmacological interventions at this time. The panel voted on whether this recommendation should be strong or weak and there was one abstention and one dissenting vote.

Recommendation: In settings where LEEP/LLETZ is available and accessible, the expert panel suggests treatment with LEEP/LLETZ over cryotherapy Population: Women with histologically confirmed CIN Intervention: Cryotherapy versus LEEP Factor Decision Explanation High or moderate evidence (is there high- or moderate-quality evidence?) The higher the quality of evidence, the more likely is a strong recommendation.  Yes  No ÅÅOO There is moderate-quality evidence from both randomized and observational controlled studies for recurrence rates. However, there is low-quality evidence for other outcomes that were considered critical and important for decision-making (e.g. severe adverse events, cervical cancer). There is uncertainty for fertility and other obstetric outcomes, and HIV acquisition/transmission was not measured. Certainty about the balance of benefits versus harms and burdens (is there certainty?) The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely is a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation. Benefits of LEEP were greater, and harms were fewer or similar Recurrence rates of CIN1, CIN2–3 and all CINs are probably greater with cryotherapy: CIN2–3, odds ratio (OR) 3.3 (CI 1.04 to 10.46) CIN1, OR 2.74 (CI 0.62 to 12.07) All CIN, OR 2.14 (CI 1.05 to 4.33). Cryotherapy may be less acceptable to patients than LEEP. There may be little difference in serious adverse events between cryotherapy and LEEP, but there may be fewer minor adverse events (such as pain) with cryotherapy. It is unclear whether there is a difference in fertility/obstetric outcomes. High value was placed on CIN recurrence, serious adverse events and acceptability to the patient. Low value was placed on minor adverse events. Certainty in or similar values (is there certainty or similarity?) The more certainty or similarity in values and preferences, the more likely is a strong recommendation. Yes  No Similar values across women There is not a lot of variability The panel felt secure in assuming the populations value Resource implications (are resources worth expected benefits?) The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision – that is, fewer resources consumed – the more likely is a strong recommendation. More resources required for LEEP Need for more skilled providers to perform LEEP Need for more or expensive equipment/supplies for LEEP; electricity supply for LEEP Need for local anaesthesia with LEEP Overall strength of recommendation Conditional

Methods Types of participants
We included studies in all populations with influenza or influenza like-illness. Types of intervention Oseltamivir, zanamivir, amantadine or rimantadine in any dose or by any route. Type of outcome measures We determined a priori to report on the following outcomes because they were judged to be important or critical for decision making: Mortality, Hospitalisation, ICU Admission, mechanical ventilation and respiratory failure, Duration of hospitalization, Time to alleviation of symptoms, Time to return to normal activity, Complications Critical adverse events (e.g. major psychotic disorders, encephalitis, stroke and seizure), Important adverse events (e.g. pain in extremities, clonic twitching, body weakness, dermatological changes such as uticaria and rash) Viral shedding and Resistance

GRADE Uptake World Health Organization
Allergic Rhinitis in Asthma Guidelines (ARIA) American Thoracic Society American College of Physicians European Respiratory Society European Society of Thoracic Surgeons British Medical Journal Infectious Disease Society of America American College of Chest Physicians UpToDate® National Institutes of Health and Clinical Excellence (NICE) Scottish Intercollegiate Guideline Network (SIGN) Cochrane Collaboration Clinical Evidence Agency for Health Care Research and Quality (AHRQ) Partner of GIN Over 60 major organizations

Recommendation 1a The panel recommends that people who had household contact with smear positive or M/XDR TB index cases be investigated for active TB (strong recommendation, very low quality evidence).

Recommendation 1b The panel recommends that people who had household contact with TB index cases who are children younger than 5 years of age be investigated for active TB (strong recommendation, very low quality evidence).

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