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Epistasis and the sensitivity of phenotypic screens for beta thalassaemia.

Penman BS, Gupta S, Weatherall DJ - Br. J. Haematol. (2014)

Bottom Line: For both of these functions it is vital that the screen performed is suitably sensitive.Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts.Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, Oxford, UK.

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Related in: MedlinePlus

Mean corpuscular volumes (MCVs) and osmotic fragility profiles for different thalassaemic genotypes. In panel (A), bars represent the mean ± 1 standard deviation for the MCV of each indicated genotype; sample sizes are indicated above each bar. Where a sample was stated to consist only of males or females, this has been indicated with ‘M’ or ‘F’. Markers lacking error bars represent reported values from single individuals of the indicated genotype. The ‘normal’ and alpha thalassaemia data are taken from Table 11·4 of Weatherall and Clegg (2001), and are MCV values for individuals >16 years of age. The beta thalassaemic and alpha-beta thalassaemic data are taken from Kanavakis et al (1982), Rosatelli et al (1984), Maccioni and Cao (1985), Sanna et al (1980) and Melis et al (1983). Sanna et al (1980) reported MCV values for alpha thalassaemic individuals defined phenotypically; we have assumed this sample to represent homozygotes for ‘−α’. The one tube osmotic fragility test (OTOFT) MCV data are from Yazdani et al (2008). Panel (B) illustrates haemolysis rates (y axis) for different concentrations of NaCl (x axis) for compound alpha-beta thalassaemia heterozygotes and normal cells (Maccioni & Cao, 1985). No distinction was made in that study between different forms of alpha thalassaemia. The Sanna et al data in panel (A) were extracted from graphs in Sanna et al (1980) using GetData Graph Digitizer. The curves in panel (B) were extracted using GetData Graph Digitizer from: Journal of Medical Genetics, Maccioni, L. & Cao, A., 22, 374–376, copyright 1985. With permission from BMJ Publishing Group Ltd.
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fig01: Mean corpuscular volumes (MCVs) and osmotic fragility profiles for different thalassaemic genotypes. In panel (A), bars represent the mean ± 1 standard deviation for the MCV of each indicated genotype; sample sizes are indicated above each bar. Where a sample was stated to consist only of males or females, this has been indicated with ‘M’ or ‘F’. Markers lacking error bars represent reported values from single individuals of the indicated genotype. The ‘normal’ and alpha thalassaemia data are taken from Table 11·4 of Weatherall and Clegg (2001), and are MCV values for individuals >16 years of age. The beta thalassaemic and alpha-beta thalassaemic data are taken from Kanavakis et al (1982), Rosatelli et al (1984), Maccioni and Cao (1985), Sanna et al (1980) and Melis et al (1983). Sanna et al (1980) reported MCV values for alpha thalassaemic individuals defined phenotypically; we have assumed this sample to represent homozygotes for ‘−α’. The one tube osmotic fragility test (OTOFT) MCV data are from Yazdani et al (2008). Panel (B) illustrates haemolysis rates (y axis) for different concentrations of NaCl (x axis) for compound alpha-beta thalassaemia heterozygotes and normal cells (Maccioni & Cao, 1985). No distinction was made in that study between different forms of alpha thalassaemia. The Sanna et al data in panel (A) were extracted from graphs in Sanna et al (1980) using GetData Graph Digitizer. The curves in panel (B) were extracted using GetData Graph Digitizer from: Journal of Medical Genetics, Maccioni, L. & Cao, A., 22, 374–376, copyright 1985. With permission from BMJ Publishing Group Ltd.

Mentions: Figure1A compares reported mean corpuscular volume (MCV) values of red blood cells from individuals carrying different combinations of thalassaemic mutations (Sanna et al, 1980; Kanavakis et al, 1982; Melis et al, 1983; Rosatelli et al, 1984; Maccioni & Cao, 1985; Weatherall & Clegg, 2001), together with the MCVs of blood samples that tested either positive or negative in a OTOFT (Yazdani et al, 2008). The low MCV of carriers of either alpha or beta thalassaemia can be elevated by the coinheritance of alpha and beta thalassaemic mutations, due to the aforementioned ameliorative effect of balancing out globin chain synthesis, such that the range of MCV values for −α/−α ββT individuals overlaps the range of MCV values that tested negative in the OTOFT. This suggests there may be a risk of −α/−α ββT individuals being missed by the OTOFT screen.


Epistasis and the sensitivity of phenotypic screens for beta thalassaemia.

Penman BS, Gupta S, Weatherall DJ - Br. J. Haematol. (2014)

Mean corpuscular volumes (MCVs) and osmotic fragility profiles for different thalassaemic genotypes. In panel (A), bars represent the mean ± 1 standard deviation for the MCV of each indicated genotype; sample sizes are indicated above each bar. Where a sample was stated to consist only of males or females, this has been indicated with ‘M’ or ‘F’. Markers lacking error bars represent reported values from single individuals of the indicated genotype. The ‘normal’ and alpha thalassaemia data are taken from Table 11·4 of Weatherall and Clegg (2001), and are MCV values for individuals >16 years of age. The beta thalassaemic and alpha-beta thalassaemic data are taken from Kanavakis et al (1982), Rosatelli et al (1984), Maccioni and Cao (1985), Sanna et al (1980) and Melis et al (1983). Sanna et al (1980) reported MCV values for alpha thalassaemic individuals defined phenotypically; we have assumed this sample to represent homozygotes for ‘−α’. The one tube osmotic fragility test (OTOFT) MCV data are from Yazdani et al (2008). Panel (B) illustrates haemolysis rates (y axis) for different concentrations of NaCl (x axis) for compound alpha-beta thalassaemia heterozygotes and normal cells (Maccioni & Cao, 1985). No distinction was made in that study between different forms of alpha thalassaemia. The Sanna et al data in panel (A) were extracted from graphs in Sanna et al (1980) using GetData Graph Digitizer. The curves in panel (B) were extracted using GetData Graph Digitizer from: Journal of Medical Genetics, Maccioni, L. & Cao, A., 22, 374–376, copyright 1985. With permission from BMJ Publishing Group Ltd.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383351&req=5

fig01: Mean corpuscular volumes (MCVs) and osmotic fragility profiles for different thalassaemic genotypes. In panel (A), bars represent the mean ± 1 standard deviation for the MCV of each indicated genotype; sample sizes are indicated above each bar. Where a sample was stated to consist only of males or females, this has been indicated with ‘M’ or ‘F’. Markers lacking error bars represent reported values from single individuals of the indicated genotype. The ‘normal’ and alpha thalassaemia data are taken from Table 11·4 of Weatherall and Clegg (2001), and are MCV values for individuals >16 years of age. The beta thalassaemic and alpha-beta thalassaemic data are taken from Kanavakis et al (1982), Rosatelli et al (1984), Maccioni and Cao (1985), Sanna et al (1980) and Melis et al (1983). Sanna et al (1980) reported MCV values for alpha thalassaemic individuals defined phenotypically; we have assumed this sample to represent homozygotes for ‘−α’. The one tube osmotic fragility test (OTOFT) MCV data are from Yazdani et al (2008). Panel (B) illustrates haemolysis rates (y axis) for different concentrations of NaCl (x axis) for compound alpha-beta thalassaemia heterozygotes and normal cells (Maccioni & Cao, 1985). No distinction was made in that study between different forms of alpha thalassaemia. The Sanna et al data in panel (A) were extracted from graphs in Sanna et al (1980) using GetData Graph Digitizer. The curves in panel (B) were extracted using GetData Graph Digitizer from: Journal of Medical Genetics, Maccioni, L. & Cao, A., 22, 374–376, copyright 1985. With permission from BMJ Publishing Group Ltd.
Mentions: Figure1A compares reported mean corpuscular volume (MCV) values of red blood cells from individuals carrying different combinations of thalassaemic mutations (Sanna et al, 1980; Kanavakis et al, 1982; Melis et al, 1983; Rosatelli et al, 1984; Maccioni & Cao, 1985; Weatherall & Clegg, 2001), together with the MCVs of blood samples that tested either positive or negative in a OTOFT (Yazdani et al, 2008). The low MCV of carriers of either alpha or beta thalassaemia can be elevated by the coinheritance of alpha and beta thalassaemic mutations, due to the aforementioned ameliorative effect of balancing out globin chain synthesis, such that the range of MCV values for −α/−α ββT individuals overlaps the range of MCV values that tested negative in the OTOFT. This suggests there may be a risk of −α/−α ββT individuals being missed by the OTOFT screen.

Bottom Line: For both of these functions it is vital that the screen performed is suitably sensitive.Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts.Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, Oxford, UK.

Show MeSH
Related in: MedlinePlus