title: A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis.
abstract: BACKGROUND
  More than 50 million people around the world are investigated for tuberculosis using sputum smear microscopy annually. This process requires repeated visits and patients often drop out.
  
  
  RESULTS
  This clinical trial of adults with cough ≥2 wk duration (in Ethiopia, Nepal, Nigeria, and Yemen) compared the sensitivity/specificity of two sputum samples collected "on the spot" during the first visit plus one sputum sample collected the following morning (spot-spot-morning [SSM]) versus the standard spot-morning-spot (SMS) scheme. Analyses were per protocol analysis (PPA) and intention to treat (ITT). A sub-analysis compared just the first two smears of each scheme, spot-spot and spot-morning. In total, 6,627 patients (3,052 SSM/3,575 SMS) were enrolled; 6,466 had culture and 1,526 were culture-positive. The sensitivity of SSM (ITT, 70.2%, 95% CI 66.5%-73.9%) was non-inferior to the sensitivity of SMS (PPA, 65.9%, 95% CI 62.3%-69.5%). Similarly, the specificity of SSM (ITT, 96.9%, 95% CI 93.2%-99.9%) was non-inferior to the specificity of SMS (ITT, 97.6%, 95% CI 94.0%-99.9%). The sensitivity of spot-spot (ITT, 63.6%, 95% CI 59.7%-67.5%) was also non-inferior to spot-morning (ITT, 64.8%, 95% CI 61.3%-68.3%), as the difference was within the selected -5% non-inferiority limit (difference ITT = 1.4%, 95% CI -3.7% to 6.6%). Patients screened using the SSM scheme were more likely to provide the first two specimens than patients screened with the SMS scheme (98% versus 94.2%, p<0.01). The PPA and ITT analysis resulted in similar results.
  
  
  CONCLUSIONS
  The sensitivity and specificity of SSM are non-inferior to those of SMS, with a higher proportion of patients submitting specimens. The scheme identifies most smear-positive patients on the first day of consultation.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN53339491. Please see later in the article for the Editors' Summary.
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom. lcuevas@liv.ac.uk
authors.forename: Luis Eduardo
authors.initials: LE
authors.lastname: Cuevas
authors.forename: Mohammed Ahmed
authors.initials: MA
authors.lastname: Yassin
authors.forename: Najla
authors.initials: N
authors.lastname: Al-Sonboli
authors.forename: Lovett
authors.initials: L
authors.lastname: Lawson
authors.forename: Isabel
authors.initials: I
authors.lastname: Arbide
authors.forename: Nasher
authors.initials: N
authors.lastname: Al-Aghbari
authors.forename: Jeevan Bahadur
authors.initials: JB
authors.lastname: Sherchand
authors.forename: Amin
authors.initials: A
authors.lastname: Al-Absi
authors.forename: Emmanuel Nnamdi
authors.initials: EN
authors.lastname: Emenyonu
authors.forename: Yared
authors.initials: Y
authors.lastname: Merid
authors.forename: Mosis Ifenyi
authors.initials: MI
authors.lastname: Okobi
authors.forename: Juliana Olubunmi
authors.initials: JO
authors.lastname: Onuoha
authors.forename: Melkamsew
authors.initials: M
authors.lastname: Aschalew
authors.forename: Abraham
authors.initials: A
authors.lastname: Aseffa
authors.forename: Greg
authors.initials: G
authors.lastname: Harper
authors.forename: Rachel Mary Anderson
authors.initials: RM
authors.lastname: de Cuevas
authors.forename: Kristin
authors.initials: K
authors.lastname: Kremer
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.forename: Carl-Michael
authors.initials: CM
authors.lastname: Nathanson
authors.forename: Jean
authors.initials: J
authors.lastname: Joly
authors.forename: Brian
authors.initials: B
authors.lastname: Faragher
authors.forename: Stephen Bertel
authors.initials: SB
authors.lastname: Squire
authors.forename: Andrew
authors.initials: A
authors.lastname: Ramsay
mesh_terms: D000328:Adult; D016000:Cluster Analysis; D003371:Cough / Q000209:etiology*; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008403:Mass Screening / Q000379:methods*; D008853:Microscopy / Q000379:methods*; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification*; D010349:Patient Compliance; D012680:Sensitivity and Specificity; D013048:Specimen Handling / Q000379:methods*; D013183:Sputum / Q000382:microbiology*; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000175:diagnosis* / Q000382:microbiology; D055815:Young Adult