Ty of making an error is represented in Figure 6 as a function of a single CRP measurement. There is at least a 20 chance of an error in risk assignment if the true CRP value lies between 1.47 mg/L and 2.53 mg/L. The chance of an error is at least 10 for all true CRP measurements lying between 1.19 mg/L and 2.81 mg/L.DiscussionThe principal findings of this study are: 1) CRP values and intergroup and intra-individual variability of CRP did not differsubstantially among 3 distinct clinical subsets of patients with CAD and an age and sex-matched group without CAD; 2) On multiple and systematic daily, weekly, monthly, and tri-monthly measurements, CRP exhibited considerable intra-individual variability; 3) This random spontaneous variability persisted despite extensive efforts to control for systematic causes; 4) From the perspective of high-risk and low-risk assignment, 46 of the study subjects did not remain consistently within a single CRP risk category (based on a 2 mg/L cutpoint), even in the absence of any change in their cardiovascular status. Our focus is the individual patient in the clinical arena and what the clinician needs to know about the variability of absolute CRP measurements for clinical decisionmaking. The individual between-months SD estimate of CRP was 0.63 mg/L, which is substantial for clinical decision-making 
with a risk 
threshold value of 2 mg/L. For example, an individual with a CRP measurement precisely at the high-risk cutoff of 2 mg/L may be expected on repeated sampling to have measurements that would lie between 0.74 mg/L and 3.26 mg/L (2 mg/L 62 SD), considerably within both low-risk and high-risk ranges. As illustrated in Figure 6, an at least 20 chance of error in risk category assignment exists for individuals whose `true’ CRP value would lie between about 1.5 mg/L and 2.5 mg/L. A substantial proportion of the subjects in this study as well as the American population [26] have values within these limits. Moreover, in an individual participant meta-analysis of 160,309 subjects from 54 prospective studies, the median baseline CRP was 1.72 mg/L. [27] Similar findings have been shown in a multiethnic study of patients presenting with a first ST-elevation myocardial infarction. [28].CRP VariabilityPotential Drivers of CRP VariabilityWe found the least variability in the 3 diurnal CRP measurements but NT-157 increasing variability over longer follow-up periods. One third of subjects, whether in the high-risk or low-risk CRP category on initial measurement, changed risk category on at least one subsequent tri-monthly measurement. The narrow variation of diurnal values is plausible since inflammation status would not usually be expected to vary over any one day in most individuals and attests both to the reliability of the measuring technique and the absence of a significant contribution of circadian variability. Most of the variability noted over the longer term could not be clearly accounted for by symptoms or events that were frequently get Tubastatin-A reported by these stable subjects on systematic questioning regardless of any change in their CRP from one measurement to the next. Marked CRP variability was often presumably due to subclinical fluctuations in inflammation/ infection status. It is likely that the variation noted in CRP values simply reflected these changes in inflammation status since in a previous study we found similar apparently spontaneous changes on serial measurement of the inflammation cytokine, interleuk.Ty of making an error is represented in Figure 6 as a function of a single CRP measurement. There is at least a 20 chance of an error in risk assignment if the true CRP value lies between 1.47 mg/L and 2.53 mg/L. The chance of an error is at least 10 for all true CRP measurements lying between 1.19 mg/L and 2.81 mg/L.DiscussionThe principal findings of this study are: 1) CRP values and intergroup and intra-individual variability of CRP did not differsubstantially among 3 distinct clinical subsets of patients with CAD and an age and sex-matched group without CAD; 2) On multiple and systematic daily, weekly, monthly, and tri-monthly measurements, CRP exhibited considerable intra-individual variability; 3) This random spontaneous variability persisted despite extensive efforts to control for systematic causes; 4) From the perspective of high-risk and low-risk assignment, 46 of the study subjects did not remain consistently within a single CRP risk category (based on a 2 mg/L cutpoint), even in the absence of any change in their cardiovascular status. Our focus is the individual patient in the clinical arena and what the clinician needs to know about the variability of absolute CRP measurements for clinical decisionmaking. The individual between-months SD estimate of CRP was 0.63 mg/L, which is substantial for clinical decision-making with a risk threshold value of 2 mg/L. For example, an individual with a CRP measurement precisely at the high-risk cutoff of 2 mg/L may be expected on repeated sampling to have measurements that would lie between 0.74 mg/L and 3.26 mg/L (2 mg/L 62 SD), considerably within both low-risk and high-risk ranges. As illustrated in Figure 6, an at least 20 chance of error in risk category assignment exists for individuals whose `true’ CRP value would lie between about 1.5 mg/L and 2.5 mg/L. A substantial proportion of the subjects in this study as well as the American population [26] have values within these limits. Moreover, in an individual participant meta-analysis of 160,309 subjects from 54 prospective studies, the median baseline CRP was 1.72 mg/L. [27] Similar findings have been shown in a multiethnic study of patients presenting with a first ST-elevation myocardial infarction. [28].CRP VariabilityPotential Drivers of CRP VariabilityWe found the least variability in the 3 diurnal CRP measurements but increasing variability over longer follow-up periods. One third of subjects, whether in the high-risk or low-risk CRP category on initial measurement, changed risk category on at least one subsequent tri-monthly measurement. The narrow variation of diurnal values is plausible since inflammation status would not usually be expected to vary over any one day in most individuals and attests both to the reliability of the measuring technique and the absence of a significant contribution of circadian variability. Most of the variability noted over the longer term could not be clearly accounted for by symptoms or events that were frequently reported by these stable subjects on systematic questioning regardless of any change in their CRP from one measurement to the next. Marked CRP variability was often presumably due to subclinical fluctuations in inflammation/ infection status. It is likely that the variation noted in CRP values simply reflected these changes in inflammation status since in a previous study we found similar apparently spontaneous changes on serial measurement of the inflammation cytokine, interleuk.
