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Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls - a hypothesis-generating pilot study.

Bäckryd E, Ghafouri B, Carlsson AK, Olausson P, Gerdle B - J Pain Res (2015)

Bottom Line: Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age.Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients).The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.

ABSTRACT
Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin-angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin-angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

No MeSH data available.


Related in: MedlinePlus

Three-dimensional score plot of group membership orthogonal partial least squares – discriminant analysis.Notes: Class separation between patients (n=11, green dots marked by [1]) and healthy controls (n=11, blue dots marked by [2]) occurs along the t[1] axis (inter-class variation), whereas the other two axes (to[1] and to[2]) represent intra-class variation.
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f1-jpr-8-321: Three-dimensional score plot of group membership orthogonal partial least squares – discriminant analysis.Notes: Class separation between patients (n=11, green dots marked by [1]) and healthy controls (n=11, blue dots marked by [2]) occurs along the t[1] axis (inter-class variation), whereas the other two axes (to[1] and to[2]) represent intra-class variation.

Mentions: In order to identify proteins discriminating between patients and healthy controls, an OPLS-DA regression model with three latent variables (one predictive interclass and two orthogonal intraclass) was computed. The model had an excellent fit (R2=0.99) and a good predictivity (Q2=0.70). Hence, clear class separation was achieved (Figure 1), and using CV-ANOVA, the model was shown to be highly significant (P=0.005). VIP computations led to the identification of 36 proteins highly associated with class discrimination (VIP ≥1.5), ie, discriminating between patients and healthy controls.


Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls - a hypothesis-generating pilot study.

Bäckryd E, Ghafouri B, Carlsson AK, Olausson P, Gerdle B - J Pain Res (2015)

Three-dimensional score plot of group membership orthogonal partial least squares – discriminant analysis.Notes: Class separation between patients (n=11, green dots marked by [1]) and healthy controls (n=11, blue dots marked by [2]) occurs along the t[1] axis (inter-class variation), whereas the other two axes (to[1] and to[2]) represent intra-class variation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492642&req=5

f1-jpr-8-321: Three-dimensional score plot of group membership orthogonal partial least squares – discriminant analysis.Notes: Class separation between patients (n=11, green dots marked by [1]) and healthy controls (n=11, blue dots marked by [2]) occurs along the t[1] axis (inter-class variation), whereas the other two axes (to[1] and to[2]) represent intra-class variation.
Mentions: In order to identify proteins discriminating between patients and healthy controls, an OPLS-DA regression model with three latent variables (one predictive interclass and two orthogonal intraclass) was computed. The model had an excellent fit (R2=0.99) and a good predictivity (Q2=0.70). Hence, clear class separation was achieved (Figure 1), and using CV-ANOVA, the model was shown to be highly significant (P=0.005). VIP computations led to the identification of 36 proteins highly associated with class discrimination (VIP ≥1.5), ie, discriminating between patients and healthy controls.

Bottom Line: Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age.Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients).The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.

ABSTRACT
Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin-angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin-angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

No MeSH data available.


Related in: MedlinePlus