Application of principal component analysis to the study of quantitative structure-activity relationships by means of multiple regression analysis.
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Models, Chemical↗
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A non-linear regression analysis program for describing electrophysiological data with multiple functions using Microsoft Excel.
The objective of this present study was to demonstrate a method for fitting complex electrophysiological data with multiple functions using the SOLVER add-in of the ubiquitous spreadsheet Microsoft Excel. SOLVER minimizes the difference between the sum of the squares of the data to be fit and the function(s) describing the data using an iterative generalized reduced gradient method. While it is a straightforward procedure to fit data with linear functions, and we have previously demonstrated a method of non-linear regression analysis of experimental data based upon a single function, it is more complex to fit data with multiple functions, usually requiring specialized expensive computer software. In this paper we describe an easily understood program for fitting experimentally acquired data, in this case the stimulus-evoked compound action potential from the mouse optic nerve, with multiple Gaussian functions. The program is flexible and can be applied to describe data with a wide variety of user-input functions.
Electronic Data Processing↗
Pancreatic adenocarcinoma: regression analysis to identify improved cytologic criteria.
The incidence of pancreatic adenocarcinoma is increasing and it is usually unresectable at the time of diagnosis. Consequently, fine-needle aspiration biopsy (FNAB) is being used more frequently for diagnosis. The reported sensitivity of diagnosing pancreatic adenocarcinoma by FNAB has varied between 50% and 100%. In an attempt to increase the diagnostic sensitivity, we retrospectively reviewed a series of pancreatic FNABs. Fifteen cytologic criteria were evaluated in 78 patients who had pancreatic FNABs. Of these patients, 49 had primary adenocarcinomas and 29 had benign, non-neoplastic lesions. Using a stepwise logistic regression analysis we identified three key cytologic criteria for this diagnosis. Our study identified anisonucleosis (P = 0.001), large nuclei (P = .007), and nuclear molding (P = .03) as the significant cytologic features for diagnosing pancreatic adenocarcinoma. In combination, these three criteria had a sensitivity of 98% and a specificity of 100%.
Adenocarcinoma↗
Amitriptyline for inpatients and SSRIs for outpatients with depression? Systematic review and meta-regression analysis.
BACKGROUND: Although the selective serotonin reuptake inhibitors (SSRIs) are widely used as first-line agents in depression, amitriptyline, a reference tricyclic (TCA) agent, has the edge in terms of efficacy over control antidepressants (ADs), but it is not clear whether this advantage can be attributed to a more favourable profile in inpatients, but not in outpatients, with depression. The aim of this study was to investigate the contribution of study setting on outcome in clinical trials comparing amitriptyline with any other AD. METHODS: A systematic review and meta-regression analysis of amitryptiline randomised clinical trials was carried out. The electronic search yielded 181 randomised clinical trials, 47% enrolling inpatients and 53% outpatients with depression. RESULTS: Both on a dichotomous and continuous out-come, amitriptyline was more effective than control agents in in-patients [Peto odds ratio (OR): 1.22, 95%, Confidence Interval (CI): 1.04, 1.42; Standardised Mean Difference (SMD): 0.28, 95 %,Cl: 0.08, 0.46], but not in outpatients (Peto OR: 1.01, 95%, CI: 0.88,1.17; SMD: 0.10,95% CI: -0.02,0.23). Among inpatients amitriptyline was significantly more effective than TCA and nonsignificantly more effective than the SSRIs. Among outpatients no statistically significant differences emerged between amitriptyline and TCA and between amitriptyline and the SSRIs. Amitriptylinewas less well tolerated than control agents in outpatients (Peto OR: 0.90, 95%, CI: 0.81, 0.99), but not in inpatients (Peto OR:1.09, 95% CI: 0.95, 1.25). CONCLUSIONS: These data suggest that a reasonable approach could be the first-line prescription of newer agents in the routine outpatient care of depressive subjects, and the use of amitriptyline in inpatients with severe depression.
Adrenergic Uptake Inhibitors↗
Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis.
OBJECTIVE: To assess the relative effect of different antihypertensive agents on proteinuria and renal function in patients with diabetes. DATA SOURCES: We used MEDLINE and bibliographies in recent articles to identify studies of the effects of antihypertensive agents on renal function in patients with diabetes. STUDY SELECTION: We selected 100 controlled and uncontrolled studies that provided data on renal function, proteinuria, or both, before and after treatment with an antihypertensive agent. DATA EXTRACTION: Data on blood pressure, renal function, proteinuria, patient characteristics (for example, age, sex, and type of diabetes), and study design (for example, random allocation and the use of a placebo) were extracted from selected studies. DATA SYNTHESIS: Multiple linear regression analysis indicated that angiotensin-converting enzyme (ACE) inhibitors decreased proteinuria independent of changes in blood pressure, treatment duration, and the type of diabetes or stage of nephropathy, as well as study design (P < 0.0001). Reductions in proteinuria from other antihypertensive agents could be entirely explained by changes in blood pressure. Blood pressure reduction in itself was associated with a relative increase in glomerular filtration rate (regression coefficient [+/- SE], 3.70 +/- .92 mL/min for each reduction of 10 mm Hg in mean arterial pressure; P = 0.0002); however, compared with other agents, ACE inhibitors had an additional favorable effect on glomerular filtration rate that was independent of blood pressure changes (3.41 +/- 1.71 mL/min; P = 0.05). CONCLUSION: Angiotensin-converting enzyme inhibitors can decrease proteinuria and preserve glomerular filtration rate in patients with diabetes. These effects occur independent of changes in systemic blood pressure.
Adolescent↗
Outcome of pregnancies complicated by severe hypertension and delivered before 34 weeks; stepwise logistic regression analysis of prognostic factors.
The outcome is described for 106 patients with severe hypertension in pregnancy requiring delivery between 26 and 34 weeks. Management was with methyldopa, hydralazine when required and delivery by caesarean section when indicated. Most patients were delivered for cardiotocographic fetal distress or unstable maternal blood pressure. Eighty-five babies (80%) survived and were well at follow-up at 1 year; the perinatal mortality was 123/1000 total births. One patient had postpartum eclampsia, one had pulmonary oedema and one had transient renal failure, but all mothers left hospital well. Stepwise logistic regression analysis showed that the primary positive factor for survival of a healthy baby was gestational age, which was strongly correlated with birthweight. The need for caesarean section as an emergency, hypotension after parenteral hydralazine, intrauterine growth retardation, and severe proteinuria were adverse factors. Intraventricular haemorrhage had a major adverse effect on neonatal survival; it was predisposed to by prolonged maternal hypertension and by low gestational age.
Adult↗
Laparoscopic cholecystectomy: what does affect the outcome? A retrospective multifactorial regression analysis.
BACKGROUND: The association between various factors and the postoperative outcome has not been thoroughly studied in laparoscopic cholecystectomy (LC). The aim of this retrospective study was to determine which factors significantly affect patients outcome after LC. METHODS: The medical and operative records of all consecutive patients who underwent LC at our institution from 1991 to 1996 were reviewed. The effect of age, medical and surgical history, duration of procedure, and setup (urgent or elective) on the postoperative complication rate and on the length of postoperative hospital stay (LOS) were analyzed using multiple linear regression and logistic regression analysis. Overall, 601 patients were included in the study. RESULTS: The factors that significantly prolonged LOS were age (p = 0.0145), acute cholecystitis (p = 0.0006), history of ischemic heart disease (p = 0.0332), and duration of procedure (p < 0.0001). A significantly higher postoperative morbidity rate was noted in patients who had a procedure longer then 2 h than in patients whose surgery required less the 2 h (13.6% vs 3.6%, respectively; p < 0.0001). Similarly, higher morbidity was noted in elderly patients than in younger patients (16% vs 6.1%; p = 0.0005). Other factors that significantly increased postoperative morbidity included acute cholecystitis (p = 0.023), a history of cholangitis (p = 0.018), and diabetes (p = 0.05). CONCLUSIONS: According to this study, advanced age, longer duration of procedure, and acute cholecystitis significantly increase both the postoperative morbidity and the LOS. History of ischemic heart disease significantly increases LOS, but does not increase morbidity after LC.
Adolescent↗
Air pollution and acute respiratory diseases in children: regression analysis of morbidity data.
The aim of this study was to investigate the relationship between acute respiratory diseases and the air quality in the urban area of the Upper Silesian Industrial Zone during autumn and winter with special emphasis on temporal variability in the air concentrations of pollutants. The survey was carried out in 5 primary care units in Chorzów where the morbidity data on the selected respiratory diseases were collected from 1 November 1992 to 31 March 1993. The air pollution data were obtained from the monitoring station, being a part of the Sanitary and Epidemiological Station Network. Regression analysis with mean values of concentrations of air pollutants as explanatory variables revealed a positive effect of combined suspended particulate matter and SO2 concentration on the increased prevalence of bronchitis and bronchiolitis. Similar and even stronger effect was observed at the level of temporal variability coefficients of the air pollutants. A hypothesis that temporal variability of the air concentration of pollutants might be a more relevant factor for determining the prevalence of respiratory diseases than simple mean values of the pollutant concentrations is very interesting worthy of further investigations.
Acute Disease↗
A step-wise logistic regression analysis of hepatocellular carcinoma. An aspiration biopsy study.
Fine needle aspiration biopsy (FNAB) has become a popular method to diagnose mass lesions of the liver. Although several reports have listed FNAB criteria to be used to diagnose both primary and metastatic tumors of the liver, none have separated key cytologic criteria from secondary criteria. We reviewed the FNAB smears from 35 patients with proven hepatocellular carcinoma and 74 patients with proven metastatic tumors in the liver. All specimens were coded as to the presence or absence of the following variables: polygonal cells with centrally placed nuclei; well-defined, granular cytoplasm; large nucleoli; small cytoplasmic vacuoles; large cytoplasmic vacuoles; bile; polymorphonuclear leukocytes; malignant cells separated by sinusoidal vessels; endothelial cells surrounding tumor cell clusters; multinucleated tumor giant cells; basophilic intracytoplasmic inclusions; eosinophilic intracytoplasmic inclusions; and intranuclear cytoplasmic inclusions. A step-wise logistic regression analysis was performed on the data to determine the variables predictive of hepatocellular carcinoma. The statistical analysis selected polygonal cells with centrally placed nuclei, malignant cells separated by sinusoidal capillaries, and bile as the key cytologic criteria for hepatocellular carcinoma. Endothelial cells surrounding tumor cell clusters and intranuclear cytoplasmic inclusions were selected as secondary criteria by this analysis.
Biopsy, Needle↗
Can patient characteristics predict the outcome of endoscopic evaluation of iron deficiency anemia: a multiple logistic regression analysis.
BACKGROUND: The purpose of this study was to identify clinical and biochemical variables that predict the outcome of upper/lower endoscopy in outpatients with iron deficiency anemia and to determine which endoscopic procedure should be performed first. METHODS: Ninety-eight patients (74 women, 24 men; mean age 55 years) with iron deficiency anemia referred from the hematology department were interviewed and responded to a questionnaire that included clinical and biochemical variables, and underwent EGD (with biopsies) and colonoscopy. The endoscopic findings were recorded as presence/absence of GI cancer, upper/lower GI tract lesions and bleeding/non-bleeding-associated GI lesions. A multiple logistic regression analysis was applied to identify variables significantly related with the outcome of the investigations. Multiple analyses were performed so that a Bonferroni correction for multiple testing removed significance except where p<0.01. RESULTS: A likely cause of iron deficiency anemia was found in 86.7% of patients. The risk factors for GI malignancies were: male gender (OR 7.5: 95% CI[1.7, 31.9]; p<0.01), advanced age (OR 1.1/y: 95% CI[1, 1.2]; p<0.01), and lower mean corpuscular volume (OR 1.1/unit: 95% CI[1, 1.2]; p<0.002). The risk factors for bleeding-related diseases were the following: greater age (OR 1.1/y: 95% CI[1.1, 1.2]; p<0.001), absence of lower-GI tract symptoms (OR 4.7: 95% CI[1.3, 16.6]; p<0.05), and a positive fecal occult blood test (OR 4.1: 95% CI[1.2, 14.3]; p<0.05). The risk factors for non-bleeding-related GI tract diseases were the following: negative fecal occult blood test (OR 4.5: 95% CI[1.16, 20]; p<0.05) and higher Hb level (OR 1.4/unit: 95% CI[1.1, 1.8]; p<0.05). CONCLUSIONS: For non-hospitalized patients with iron deficiency anemia, colonoscopy should be the initial investigation in those greater than 50 years of age, particularly men, and those without upper-GI tract symptoms and with lower values for mean corpuscular volume and Hb. EGD should be performed first in younger patients, particularly those with a mild decrease in Hb and a negative fecal occult blood test.
Age Factors↗
Multiple regression analysis of relationship between frontal lobe phosphorus metabolism and clinical symptoms in patients with schizophrenia.
We investigated the differences among diagnostic types of 36 schizophrenic patients in the brain phosphorus metabolism in the frontal lobe. We performed phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in the frontal region in patients with schizophrenia of the catatonic (n = 4), disorganized (n = 8), paranoid (n = 10) and undifferentiated (n = 14) types. In the disorganized type, the PME level was significantly decreased compared to those in the other three types, while the phosphodiester (PDE) level tended to be higher, although not significantly, than those in the other types. Using multiple regression analysis, we investigated whether or not the clinical symptoms were correlated with the brain phosphorus metabolism. An increased motor retardation factor score was significantly correlated with decreased PME level, whereas more severe emotional withdrawal and blunted affect were associated with increased PDE level. These results suggest that altered membrane phospholipid metabolism in the frontal region may be associated with negative symptoms and that schizophrenia of the disorganized type is associated with more severe negative symptoms and may present more severe brain abnormalities compared to the other types.
Adolescent↗
Factors associated with the difference in score between women's and doctors' decisional conflict about hormone therapy: a multilevel regression analysis.
OBJECTIVE: To explore factors associated with the difference in score between women's and doctors' decisional conflict about hormone therapy (HT). DESIGN: Secondary analysis. SETTING AND PARTICIPANTS: family doctors were randomized to prepare women for counselling about HT using either a decision aid or a pamphlet. MAIN VARIABLES STUDIED: After each counselling session, decisional conflict was assessed in women and doctors using the Decisional Conflict Scale (DCS) and the Provider Decision Process Assessment Instrument (PDPAI), respectively. The difference in score between the DCS and PDPAI was computed and entered as the dependent variable in a multilevel regression analysis. MAIN OUTCOME RESULTS: A total of 40 doctors and 167 women were included in the analysis. The intra-doctor correlation coefficient was 0.25. Factors associated with women experiencing higher decisional conflict than their doctor were: age of doctor >45 years, women who were undecided about the best choice after the counselling session, women with a university degree and women who said that their doctor usually does not give them control over treatment decision. Factors associated with doctors experiencing more decisional conflict than women were: doctors who were undecided about the quality of the decision, length of visit <30 min and women who thought that the decision was shared with their doctor. CONCLUSION: In order to reduce the disparities between women's and doctors' decisional conflict about HT, interventions aimed at raising awareness of doctors about shared decision-making should be encouraged.
Canada↗
Prediction of late results following valve replacement in aortic valve stenosis. Seventeen years of follow-up examined with the Cox regression analysis.
A total of 122 patients (mean age: 55 years, range 20-75 years) were alive 30 days after isolated aortic valve replacement (AVR) performed in 1965-73 for aortic valve stenosis (AS). Cold chemical Bretschneider cardioplegia was used in all operations. The maximum follow-up was 17 years, mean 9 years. The 10-year cumulative survival +/- SE was 63 +/- 4%. Twenty-one preoperative clinical, invasive and valve-related variables were entered into a Cox regression analysis. Variables with independent predictive value regarding long-term survival were: Left ventricular failure (regression coefficient: b = 1.078, p less than 0.0002), age (b = 0.749, p less than 0.009), pulse pressure (b = -0.663, p less than 0.02) and cardio-thoracic index (CTI) (b = 0.603, p less than 0.04). Based on these variables, a prognostic index with 16 different risk groups was made. In the "best" group (n = 8), the observed 10-year survival +/- SE was 88 +/- 11%, compared to 13 +/- 12% for the "worst" group (n = 8). Multivariate analysis of complication-free survival showed that the total valve-related complication-rate (VRC) (4.2/100 pat.-yrs) was influenced by valve type (Starr-Edwards ball valves, n = 118, versus Lillehei-Kaster and Smeelof-Cutter valves, n = 4) and CTI. The valve- and heart-related events (VRC together with late myocardial infarctions and pacemaker implantations, 6.5/100 pat.-yrs) depended on CTI and previous myocardial infarction. No predictors of thromboembolism (1.6/100 pat.-yrs) or coumarin-related hemorrhage (1.8/100 pat.-yrs) could be identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Comparative study of retinal nerve fiber layer measurement by StratusOCT and GDx VCC, II: structure/function regression analysis in glaucoma.
PURPOSE: To evaluate the structure/function relationship between visual field sensitivity and retinal nerve fiber layer (RNFL) thickness measured by StratusOCT (Carl Zeiss Meditec, Inc., Dublin, CA) and GDx VCC (Laser Diagnostic Technologies, Inc., San Diego, CA). METHODS: Eighty-nine subjects (27 who had healthy eyes, 21 who were glaucoma suspect, 41 who had glaucoma) were enrolled in this cross-sectional study. RNFL thickness was measured using the StratusOCT and the GDx VCC, and visual field (VF) was examined using the Humphrey VF analyzer. The relationship between RNFL thickness and VF sensitivity-expressed in terms of mean deviation (MD) in decibel (dB) scale, unlogged 1/lambert (L), and Advanced Glaucoma Intervention Study (AGIS) and Collaborative Initial Glaucoma Treatment Study (CIGTS) VF scores-were evaluated with linear and nonlinear regression models. Coefficient of determination (R(2)) was calculated, and regression models were compared using the Akaike information criterion and the F test. RESULTS: In plotting MD against RNFL thickness, curvilinear regression models demonstrated the best fit, whereas linear regression attained the best associations when VF sensitivity was expressed in 1/L. However, when healthy subjects were excluded from the analyses, the second-order polynomial was better than linear regression in describing the relation between 1/L and GDx VCC-measured RNFL thickness. Regression profiles between AGIS/CIGTS VF scores and RNFL thickness were best described in the linear and the first-order inverse models for GDx VCC and StratusOCT RNFL measurements, respectively. In general, StratusOCT RNFL measurements achieved higher associations with visual function in all the respective regression analyses than did GDx VCC. CONCLUSIONS: Description of structure/function relationships in glaucoma depends on the choice of perimetry scale, the type of RNFL measuring device, and the characteristics of the studied groups. The higher association with visual function in StratusOCT RNFL measurements compared with that in GDx VCC suggested optical coherence tomography might be a better approach for evaluating structure/function relationships. Curvilinear regression profiles found between StratusOCT RNFL thickness and MD/VF scores provide an explanation for those longitudinal observations, showing that VFs with higher AGIS/CIGTS VF scores or worse MD at baseline are at higher risk for deterioration. Regression analysis of the structure/function profile could provide important information in the assessment of the trend and pattern of glaucoma progression.
Disease Progression↗
Computer-assisted nonlinear regression analysis of the multicomponent glucose uptake kinetics of Saccharomyces cerevisiae.
The kinetics of glucose uptake in Saccharomyces cerevisiae are complex. An Eadie-Hofstee (rate of uptake versus rate of uptake over substrate concentration) plot of glucose uptake shows a nonlinear form typical of a multicomponent system. The nature of the constituent components is a subject of debate. It has recently been suggested that this nonlinearity is due to either a single saturable component together with free diffusion of glucose or a single constitutive component with a variable Km, rather than the action of multiple hexose transporters. Genetic data support the existence of a family of differentially regulated glucose transporters, encoded by the HXT genes. In this work, kinetic expressions and nonlinear regression analysis, based on an improved zero trans-influx assay, were used to address the nature of the components of the transport system. The results indicate that neither one component with free diffusion nor a single permease with a variable Km can explain the observed uptake rates. Results of uptake experiments, including the use of putative alternative substrates as inhibitory compounds, support the model derived from genetic analyses of a multicomponent system with at least two components, one a high-affinity carrier and the other a low-affinity carrier. This approach was extended to characterize the activity of the SNF3 protein and identify its role in the depression of high-affinity uptake. The kinetic data support a role of SNF3 as a regulatory protein that may not itself be a transporter.
Biological Transport↗
Early and late recurrences after gastrectomy for gastric cancer: a multiple logistic regression analysis.
PURPOSE: Although many studies have focused on clinical risk factors for prognosis of patients with surgically treated gastric cancer, little information is available regarding the timing of recurrent malignant disease. The purpose of this study was to determine the factors that are predictive of early and late recurrences after gastrectomy. PATIENTS AND METHODS: We reviewed the hospital records of patients with hisotological proof of gastric cancer who were admitted to Sendai National Hospital during the period from 1985 to 1995. A total of 923 records were examined, and 251 patients with recurrent disease were identified. The patients were divided into an "early recurrence group" consisting of 195 patients (died within one year after surgery) and a "late recurrence group" of 56 patients (died two years or more after surgery). Clinicopathological characteristics were examined, and independent risk factors influencing the timing of recurrence were determined by a multiple logistic regression analysis. RESULTS: The mean tumor size of early recurrence cases was larger than that of late recurrence cases (p=0.0294). Tumors penetrating the serosa with direct invasion to continuous structures were found more frequently in the early recurrence group than in the late recurrence group. The patients with early recurrence showed a higher tendency to have nodal involvement, lymphatic invasion and vascular invasion. The relative risks of early and late recurrences associated with different variables were estimated by a multiple logistic regression method. The following variables were found to be significant risk factors for early recurrence: male gender (p=0.0382), lymph node metastasis (p=0.0016), and vascular invasion (p=0.0006). CONCLUSION: Male patients who have node-positive gastric cancer with vascular invasion have a high risk of early recurrence.
Female↗
Relative contribution of various expressions of cAMP excretion to other indices of parathyroid function, as tested by discriminant multivariate linear regression analysis.
We evaluated the relative contribution to the diagnosis of hyperparathyroid disease from current laboratory indices of parathyroid function--plasma calcium (I), phosphate (II), carboxy-terminal (III) and predominantly amino-terminal (IV) radioimmunoassays of parathyrin, the urinary excretion ratios of cyclic adenosine monophosphate (cAMP) to creatinine (V) or to glomerular filtrate (VI), and the ratio of the nephrogenous fraction of cAMP to glomerular filtrate (VII)--in 224 subjects: 40 with surgically proven hyperparathyroid disease, the others normoparathyroid. The decreasing order of sensitivity was I greater than VI greater than VII greater than V greater than III greater than IV greater than II; all these indices differed significantly between normoparathyroid and hyperparathyroid patients. The decreasing order of specificity was VII, III greater than I greater than IV greater than V, II greater than VI. Discriminant multivariate linear regression analysis was performed in a subset of 58 subjects (17 hyper- and 41 normoparathyroid) from the population studied here, chosen because all of the laboratory indices were determined for each subject. The classification accuracy was 98.3% for combining I, VII, and III (r = 0.908), or I and V (r = 0.893), or I and VII (r = 0.889). The other variables did not add to the precision of classification.
Adult↗
A regression analysis study of the primary somatosensory cortex during pain.
Several functional imaging studies of pain, using a number of different experimental paradigms and a variety of reference states, have failed to detect activations in the somatosensory cortices, while other imaging studies of pain have reported significant activations in these regions. The role of the somatosensory areas in pain processing has therefore been debated. In the present study the left hand was immersed in painfully cold water (standard cold pressor test) and in nonpainfully cold water during 2 min, and PET-scans were obtained either during the first or the second minute of stimulation. We observed no significant increase of activity in the somatosensory regions when the painful conditions were directly compared with the control conditions. In order to better understand the role of the primary somatosensory cortex (S1) in pain processing we used a regression analysis to study the relation between a ROI (region of interest) in the somatotopic S1-area for the stimulated hand and other regions known to be involved in pain processing. We hypothesized that although no increased activity was observed in the S1 during pain, this region would change its covariation pattern during noxious input as compared to the control stimulation if it is involved in or affected by the processing of pain. In the nonpainful cold conditions widespread regions of the ipsilateral and contralateral somatosensory cortex showed a positive covariation with the activity in the S1-ROI. However, during the first and second minute of pain this regression was significantly attenuated. During the second minute of painful stimulation there was a significant positive covariation between the activity in the S1-ROI and the other regions that are known to be involved in pain processing. Importantly, this relation was significantly stronger for the insula and the orbitofrontal cortex bilaterally when compared to the nonpainful state. The results indicate that the S1-cortex may be engaged in or affected by the processing of pain although no differential activity is observed when pain is compared with the reference condition.
Brain Mapping↗