Effect Sizes in Experimental Pain Produced by Gender, Genetic Variants and Sensitization Procedures

Background: Various effects on pain have been reported with respect to their statistical significance, but a standardized measure of effect size has been rarely added. Such a measure would ease comparison of the magnitude of the effects across studies, for example the effect of gender on heat pain with the effect of a genetic variant on pressure pain. Methodology/Principal Findings: Effect sizes on pain thresholds to stimuli consisting of heat, cold, blunt pressure, punctuate pressure and electrical current, administered to 125 subjects, were analyzed for 29 common variants in eight human genes reportedly modulating pain, gender and sensitization procedures using capsaicin or menthol. The genotype explained 0–5.9% of the total interindividual variance in pain thresholds to various stimuli and produced mainly small effects (Cohen's d 0–1.8). The largest effect had the TRPA1 rs13255063T/rs11988795G haplotype explaining >5% of the variance in electrical pain thresholds and conferring lower pain sensitivity to homozygous carriers. Gender produced larger effect sizes than most variant alleles (1–14.8% explained variance, Cohen's d 0.2–0.8), with higher pain sensitivity in women than in men. Sensitization by capsaicin or menthol explained up to 63% of the total variance (4.7–62.8%) and produced largest effects according to Cohen's d (0.4–2.6), especially heat sensitization by capsaicin (Cohen's d = 2.6). Conclusions: Sensitization, gender and genetic variants produce effects on pain in the mentioned order of effect sizes. The present report may provide a basis for comparative discussions of factors influencing pain

Effect sizes, expressed as absolute values of Cohen's d [15], of the genetics factors on pain thresholds.

<p>The recessive hereditary model was used, i.e., assigning heterozygous subjects to the group of homozygous mutated carriers. The effect sizes are given in italic letters when they were larger than those of gender, and in bold letters when exceeding a value of 0.8 indicating a large effect.</p

Effect sizes, expressed as percentage of the total variance explained by the genetic factors, on pain thresholds.

#<p>MAF: Observed minor allelic frequencies. “Minor” refers to the allele reported to be minor in gene databases. When its reported allelic frequency is close to 50%, it can happen that the “minor” allele has a frequency >50% in the actual cohort. We nevertheless preserved the denomination “minor” to be consistent with SNP databases.</p><p>The reference and the observed allelic frequencies are given, and the recessive hereditary model was used, i.e., assigning heterozygous subjects to the group of homozygous mutated carriers. The effect sizes are given in italic letters when they were larger than those of gender, and in bold letters when exceeding, arbitrarily chosen, 5%.</p

Observed thresholds to different pain stimuli and sizes of modulatory effects.

<p><b>Left</b> part: Single values of the measured pain thresholds to various stimuli are shown as dots, with statistical summaries in overlaid box plots. The boxes span the 25^th to 75^th percentiles, with the median crossing the box as a horizontal line, and the whiskers spanning values within 1.5 times the 25^th to 75^th percentiles. The subject's gender is indicated by different symbols and colors (men: red circles, women: blue crosses). At the <b>right</b> of each thresholds presentation, the effect sizes of the genetic variants obtained using the dominant hereditary model (blue filled circles), i.e., heterozygous and homozygous carriers of the variant alleles versus wild type subjects, and the recessive model (red empty circles), i.e., homozygous carriers of the variant versus the other subjects, are shown as correlation plots between the fraction of the total variance in the respective threshold explained by the respective factor and Cohen's d of that factor. An absolute value of d = 0.2 indicates a small effect, values around 0.5 a medium and above 0.8 a large effect <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017724#pone.0017724-Cohen1" target="_blank">[15]</a>. In addition, the effects sizes of gender (green filled triangles) and sensitization (orange filled squares) by capsaicin (heat, von Frey hair punctate pressure) or menthol (cold) are shown. Note that the axis scaling is non-uniform among panels to enhance data visibility. At the bottom, the overall effect sizes (all Cohen's d per condition genetics, gender or sensitization) of all analyzed factors and stimuli are grouped for genetic, gender and sensitization influences on pain thresholds, showing decreasing sizes of effects in the order sensitization, gender and genetics.</p

Effect sizes, expressed as absolute values of Cohen's d [15], of the respective factor on pain thresholds.

<p>In the case of the genetic factors, the dominant hereditary model was used, i.e., assigning heterozygous subjects to the group of wild-type subjects. The effect sizes are given in italic letters when they were larger than those of gender, and in bold letters when exceeding a value of 0.8 indicating a large effect.</p

Effect sizes, expressed as percentage of the total variance explained by the respective factor, on pain thresholds.

#<p>MAF: Observed minor allelic frequencies. “Minor” refers to the allele reported to be minor in gene databases. When its reported allelic frequency is close to 50%, it can happen that the “minor” allele has a frequency >50% in the actual cohort. We nevertheless preserved the denomination “minor” to be consistent with SNP databases.</p><p>In the case of the genetic factors, the reference and the observed allelic frequencies are given, and the dominant hereditary model was used, i.e., assigning heterozygous subjects to the group of wild-type carriers. The effect sizes are given in italic letters when they were larger than those of gender, and in bold letters when exceeding, arbitrarily chosen, 5%.</p