Department of Medical Biochemistry, Oslo University Hospital, Rikshospitalet, Oslo, Norway;
Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
Clin Chem. 2015 May;61(5):760-8. doi: 10.1373/clinchem.2014.235564. Epub 2015 Mar 10.
Urinary concentrations of creatine and guanidinoacetic acid divided by creatinine are informative markers for cerebral creatine deficiency syndromes (CDSs). The renal excretion of these substances varies substantially with age and sex, challenging the sensitivity and specificity of postanalytical interpretation.
Results from 155 patients with CDS and 12 507 reference individuals were contributed by 5 diagnostic laboratories. They were binned into 104 adjacent age intervals and renormalized with Box-Cox transforms (Ξ). Estimates for central tendency (μ) and dispersion (σ) of Ξ were obtained for each bin. Polynomial regression analysis was used to establish the age dependence of both μ[log(age)] and σ[log(age)]. The regression residuals were then calculated as z-scores = {Ξ - μ[log(age)]}/σ[log(age)]. The process was iterated until all z-scores outside Tukey fences ±3.372 were identified and removed. Continuous percentile charts were then calculated and plotted by retransformation.
Statistically significant and biologically relevant subgroups of z-scores were identified. Significantly higher marker values were seen in females than males, necessitating separate reference intervals in both adolescents and adults. Comparison between our reconstructed reference percentiles and current standard age-matched reference intervals highlights an underlying risk of false-positive and false-negative events at certain ages.
Disease markers depending strongly on covariates such as age and sex require large numbers of reference individuals to establish peripheral percentiles with sufficient precision. This is feasible only through collaborative data sharing and the use of appropriate statistical methods. Broad application of this approach can be implemented through freely available Web-based software.
尿中肌酸和胍基乙酸与肌酐的比值是脑肌酸缺乏综合征（CDS）的有价值的标志物。这些物质的肾脏排泄量随年龄和性别有很大差异，这对分析后解释的敏感性和特异性提出了挑战。
来自 5 个诊断实验室的 155 名 CDS 患者和 12507 名参考个体的结果被纳入研究。他们被分为 104 个相邻的年龄区间，并使用 Box-Cox 变换（Ξ）进行重新归一化。对于每个区间，都获得了 Ξ的中心趋势（μ）和离散度（σ）的估计值。使用多项式回归分析建立了μ[log(age)]和σ[log(age)]随年龄的依赖性。然后计算回归残差作为 z 分数={Ξ-μ[log(age)]}/σ[log(age)]。该过程迭代进行，直到所有 z 分数超出 Tukey 围栏±3.372 被识别并删除。然后通过重新转换计算并绘制连续百分位数图表。
确定了具有统计学意义和生物学相关性的 z 分数亚组。女性的标志物值明显高于男性，这需要在青少年和成人中分别建立参考区间。我们重建的参考百分位数与当前标准年龄匹配的参考区间的比较突出了在某些年龄存在假阳性和假阴性事件的潜在风险。
强烈依赖协变量（如年龄和性别）的疾病标志物需要大量的参考个体来建立具有足够精度的外周百分位数。这只有通过协作数据共享和使用适当的统计方法才能实现。这种方法的广泛应用可以通过免费的基于网络的软件来实现。
