Table 1

Study characteristics

SourceNPatients or familiesUnrelated patientsYearCountryStudy cohortMutation analyses methods: intron 1 and 22 inversion screening and mutation analysisMutation detection rate, %EthnicityFrequency inhibitor screeningInhibitor assayTreated > 50 EDUnselected cohortHigh quality
Ahmed14  46 Patients Yes 2005 New Delhi, India Single PCR, DHPLC 92 NA NA Bethesda NA NA − 
Awidi15  117 Patients No 2010 Jordan NA PCR sequencing NA NA NA Bethesda Incl < 50 ED NA − 
Boekhorst16  664 Patients NA 2008 Nijmegen, the Netherlands Paris, France Tehran, Iran Multi PCR-DGGE/CSGE sequencing 100 NA NA Bethesda or Nijmegen Bethesda Incl < 50 ED No − 
Casaña17  92 Families Yes 2008 Valencia, Spain Single Southern-blot/PCR sequencing 100 NA NA Bethesda NA NA − 
Castaman18  27 Patients No 2007 Albany Single PCR, DHPLC sequencing 100 NA 18 patients screened once NA Minimally treated NA − 
Chen19  88 Patients Yes 2010 Taipei, Taiwan Single PCR, DHPLC sequencing, RNA analysis 98 NA NA Bethesda NA Yes − 
David20  108 Patients Yes 2006 Lisboa/Porto, Portugal Multi PCR, SSCP/restriction enzyme cleavage/sequencing 100 White NA Bethesda NA NA − 
Fernandez-Lopez21  55 Patients Yes 2005 Andalusia, Spain Single PCR sequencing 89 NA NA NA Na Yes − 
Goodeve22  49 Patients NA 2000 Recombinate Study Group* Multi Southern-blot, CSGE sequencing 93 31 white, 7 African American, 4 Hispanic, 1 Asian, 1 other, 1 unknown At least every 3 months, ≥ 0.6 BU/mL Bethesda Incl < 50 ED No − 
Gouw23  122 Patients No 2007 Leuven, Madrid, Stockholm, Malmö, Montreal, Göteborg Multi NA 83 151 white, 1 African American, 3 Asian, 7 other, 1 unknown Various frequency of testing, ≥ 2 positive inhibitor and decreased recovery Bethesda or Nijmegen Bethesda All > 50 ED Yes + 
Gouw24  318 Patients No 2010 Utrecht, The Netherlands Single Southern blot/PCR sequencing 95 NA ≥ 1/y (1970-1980), ≥ 1/6 m (early 1990s), ≥ 1/3 m (late 1990s onwards) and at clinical indication; ≥ 2 positive inhibitor and decreased recovery Bethesda or Nijmegen modification All > 50 ED Yes + 
Green25  248 Patients No 2008 United Kingdom† Multi Southern blot/PCR, fluorescent solid-phase CCM/DHPLC sequencing 99 NA Various frequency of testing, clinically relevant inhibitors NA NA Yes − 
Hill26  28 Patients No 2005 Nottingham, United Kingdom Single PCR, CSGE/DHPLC sequencing NA NA NA NA NA Yes − 
Ivaskevicius27  50 Patients Yes 2001 Lithuania Single Southern blot, DGGE/CMC/DHPLC sequencing 98 NA NA Nijmegen Bethesda NA Yes − 
Jayandharan28  92 Patients Yes 2005 Vellore, India Single PCR, CSGE sequencing 93 Asian NA Bethesda Many < 50ED Yes − 
Liu29,30  708 Patients No 2008 Seattle, US‡ Single Southern blot, heteroduplex screening/restriction enzyme cleavage sequencing 99 NA Before mid1980s, tested if clinical suspicion; later more frequently Bethesda Almost all > 50 ED Yes + 
Ma31  21 Patients Yes 2008 Changhua, Taiwan Single PCR sequencing 95 Asian NA NA NA Yes − 
Margaglione32  971 Patients Yes 2008 Italy§ Multi PCR, DHPLC/CSGE sequencing 89 NA NA NA NA Yes − 
Miller33  407 Patients NA 2010 12 US centers Multi PCR sequencing 96 35 black non-Hispanic, 32 Hispanic, 321 white non-Hispanic At study entry, annually, at product switch, clinical indication Nijmegen Bethesda NA NA + 
Oldenburg34  917 Patients NA 2011 Bonn, Germany Multi CCM/DGGE sequencing 97 NA Regularly, various frequencies Various Majority > 50 ED Yes + 
Owaidah35  20 Patients No 2009 Saudi Arabia Single PCR sequencing 100 Arab At presentation, at least twice annually Bethesda Incl < 50 ED No − 
Pieneman36  25 Patients Yes 1995 Leiden, the Netherlands Single PCR, SSCP/DSCP sequencing 84 NA NA NA NA NA − 
Reitter37  155 Patients No 2010 Austria# Multi PCR sequencing 99 NA NA NA Incl < 50 ED Yes − 
Repesse38  59 Patients No 2007 Caen, France Single PCR sequencing 100 NA NA Nijmegen Bethesda NA No − 
Rosetti39  88 Patients No 2007 Buenos Aires, Argentina Single Southern blot/PCR, CSGE sequencing 95 NA NA NA NA NA − 
Sanna40  108 Patients Yes 2008 Naples, Isernia, Italy Single PCR sequencing 94 NA NA NA NA NA − 
Sirocova41  29 Patients Yes 2009 Chisinau, Moldovia Single PCR, heteroduplex screening sequencing 100 NA NA Bethesda Incl < 50 ED Yes − 
Vidal42  38 Patients Yes 2001 Barcelona, Spain Single PCR sequencing 97 White NA NA NA NA − 
Viel43  48 Patients No 2009 Atlanta, Birmingham, Augusta, Jackson, US Multi PCR sequencing 96 African American Annually Nijmegen Bethesda, ≥ once > 0.6 BU/mL NA No − 
Xue44  111 Patients Yes 2010 Tianjin, China Single PCR sequencing 97 Asian Once measured Bethesda Incl < 50 ED NA − 
SourceNPatients or familiesUnrelated patientsYearCountryStudy cohortMutation analyses methods: intron 1 and 22 inversion screening and mutation analysisMutation detection rate, %EthnicityFrequency inhibitor screeningInhibitor assayTreated > 50 EDUnselected cohortHigh quality
Ahmed14  46 Patients Yes 2005 New Delhi, India Single PCR, DHPLC 92 NA NA Bethesda NA NA − 
Awidi15  117 Patients No 2010 Jordan NA PCR sequencing NA NA NA Bethesda Incl < 50 ED NA − 
Boekhorst16  664 Patients NA 2008 Nijmegen, the Netherlands Paris, France Tehran, Iran Multi PCR-DGGE/CSGE sequencing 100 NA NA Bethesda or Nijmegen Bethesda Incl < 50 ED No − 
Casaña17  92 Families Yes 2008 Valencia, Spain Single Southern-blot/PCR sequencing 100 NA NA Bethesda NA NA − 
Castaman18  27 Patients No 2007 Albany Single PCR, DHPLC sequencing 100 NA 18 patients screened once NA Minimally treated NA − 
Chen19  88 Patients Yes 2010 Taipei, Taiwan Single PCR, DHPLC sequencing, RNA analysis 98 NA NA Bethesda NA Yes − 
David20  108 Patients Yes 2006 Lisboa/Porto, Portugal Multi PCR, SSCP/restriction enzyme cleavage/sequencing 100 White NA Bethesda NA NA − 
Fernandez-Lopez21  55 Patients Yes 2005 Andalusia, Spain Single PCR sequencing 89 NA NA NA Na Yes − 
Goodeve22  49 Patients NA 2000 Recombinate Study Group* Multi Southern-blot, CSGE sequencing 93 31 white, 7 African American, 4 Hispanic, 1 Asian, 1 other, 1 unknown At least every 3 months, ≥ 0.6 BU/mL Bethesda Incl < 50 ED No − 
Gouw23  122 Patients No 2007 Leuven, Madrid, Stockholm, Malmö, Montreal, Göteborg Multi NA 83 151 white, 1 African American, 3 Asian, 7 other, 1 unknown Various frequency of testing, ≥ 2 positive inhibitor and decreased recovery Bethesda or Nijmegen Bethesda All > 50 ED Yes + 
Gouw24  318 Patients No 2010 Utrecht, The Netherlands Single Southern blot/PCR sequencing 95 NA ≥ 1/y (1970-1980), ≥ 1/6 m (early 1990s), ≥ 1/3 m (late 1990s onwards) and at clinical indication; ≥ 2 positive inhibitor and decreased recovery Bethesda or Nijmegen modification All > 50 ED Yes + 
Green25  248 Patients No 2008 United Kingdom† Multi Southern blot/PCR, fluorescent solid-phase CCM/DHPLC sequencing 99 NA Various frequency of testing, clinically relevant inhibitors NA NA Yes − 
Hill26  28 Patients No 2005 Nottingham, United Kingdom Single PCR, CSGE/DHPLC sequencing NA NA NA NA NA Yes − 
Ivaskevicius27  50 Patients Yes 2001 Lithuania Single Southern blot, DGGE/CMC/DHPLC sequencing 98 NA NA Nijmegen Bethesda NA Yes − 
Jayandharan28  92 Patients Yes 2005 Vellore, India Single PCR, CSGE sequencing 93 Asian NA Bethesda Many < 50ED Yes − 
Liu29,30  708 Patients No 2008 Seattle, US‡ Single Southern blot, heteroduplex screening/restriction enzyme cleavage sequencing 99 NA Before mid1980s, tested if clinical suspicion; later more frequently Bethesda Almost all > 50 ED Yes + 
Ma31  21 Patients Yes 2008 Changhua, Taiwan Single PCR sequencing 95 Asian NA NA NA Yes − 
Margaglione32  971 Patients Yes 2008 Italy§ Multi PCR, DHPLC/CSGE sequencing 89 NA NA NA NA Yes − 
Miller33  407 Patients NA 2010 12 US centers Multi PCR sequencing 96 35 black non-Hispanic, 32 Hispanic, 321 white non-Hispanic At study entry, annually, at product switch, clinical indication Nijmegen Bethesda NA NA + 
Oldenburg34  917 Patients NA 2011 Bonn, Germany Multi CCM/DGGE sequencing 97 NA Regularly, various frequencies Various Majority > 50 ED Yes + 
Owaidah35  20 Patients No 2009 Saudi Arabia Single PCR sequencing 100 Arab At presentation, at least twice annually Bethesda Incl < 50 ED No − 
Pieneman36  25 Patients Yes 1995 Leiden, the Netherlands Single PCR, SSCP/DSCP sequencing 84 NA NA NA NA NA − 
Reitter37  155 Patients No 2010 Austria# Multi PCR sequencing 99 NA NA NA Incl < 50 ED Yes − 
Repesse38  59 Patients No 2007 Caen, France Single PCR sequencing 100 NA NA Nijmegen Bethesda NA No − 
Rosetti39  88 Patients No 2007 Buenos Aires, Argentina Single Southern blot/PCR, CSGE sequencing 95 NA NA NA NA NA − 
Sanna40  108 Patients Yes 2008 Naples, Isernia, Italy Single PCR sequencing 94 NA NA NA NA NA − 
Sirocova41  29 Patients Yes 2009 Chisinau, Moldovia Single PCR, heteroduplex screening sequencing 100 NA NA Bethesda Incl < 50 ED Yes − 
Vidal42  38 Patients Yes 2001 Barcelona, Spain Single PCR sequencing 97 White NA NA NA NA − 
Viel43  48 Patients No 2009 Atlanta, Birmingham, Augusta, Jackson, US Multi PCR sequencing 96 African American Annually Nijmegen Bethesda, ≥ once > 0.6 BU/mL NA No − 
Xue44  111 Patients Yes 2010 Tianjin, China Single PCR sequencing 97 Asian Once measured Bethesda Incl < 50 ED NA − 

ED indicates exposure days; NA, not available; DGGE, denaturing gradient gel electrophoresis; CSGE, conformation sensitive gel electrophoresis; DHPLC, denaturing high performance liquid chromatography; SSCP, single-strand conformation polymorphism analysis; CCM, chemical cleavage of mismatch; CMC, chemical mismatch cleavage; and DSCP, double-strand conformation polymorphism.

*

Recombinate PUP study group: East Lansing, MI; Cleveland, OH; Morgantown, WV; Chapel Hill, NC; San Juan, PR, Washington, DC; Cincinnati, OH; Denver, CO; New York, NY; New Brunswick, NJ; Las Vegas, NV; Wauwatosa, WI; Louisville, KY; Norfolk, VA; Chicago, IL; Los Angeles, CA; Summit, NJ; Lexington, KY; Iowa City, IA; Paris (Bicetre); Paris (Necker); Milan; Vicenza; Copenhagen; and Aarhus.

†

United Kingdom National Database: Bangor, Basingstoke, Bath, Bournemouth, Bristol, Cambridge, Canterbury, Cardiff, Colchester, Exeter, Gillingham, Glasgow, Leeds, Liverpool, London (Hammersmith, Lewisham, Royal Free, Royal London, and St Georges), Manchester, Norwich, Oxford, Peterborough, Plymouth, Portsmouth, Southampton, Swansea, Taunton, Truro, and Yeovil.

‡

Alaska, Arizona, California, Colorado, Georgia, Hawaii, Idaho, Indiana, Massachusetts, Michigan, Missouri, Montana, New Hampshire, New Mexico, New York, Oregon, Pennsylvania, Texas, Utah, and Vermont.

§

AICE (Italian Association of Hemophilia Centers) database: Alessandria, Arezzo, Bari, Bologna, Cagliari, Castelfranco Veneto, Catania, Catanzaro, Cesena, Cosenza, Cremona, Ferrara, Faenza, Florence, Genoa, Ivrea, L'Aquila, Latina, Macerata, Milan, Modena, Naples, Orvieto, Padua, Palermo, Parma, Pavia, Perugia, Pescara, Piacenza, Ravenna, Reggio Calabria, Reggio Emilia, Rome, Sassari, Torino, Turin, Trento, Udine, Vallo della Lucania, Verona, and Vicenza.

Atlanta, GA; Ann Arbor, MI; Worcester, MA; Iowa City, IA; Richmond, VA; Nashville, TN; Indianapolis, IN; Peoria, IL; Kansas City, MO; Aurora, CO; and Phoenix, AZ.

#

Bregenz, Dornbirn, Graz, Innsbruck, Klagenfurt, Linz, Salzburg, St Poelten, and Vienna.

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