Thorpe Jason D, Duan Xiaobo, Forrest Robin, Lowe Kimberly, Brown Lauren, Segal Elliot, Nelson Brad, Anderson Garnet L, McIntosh Martin, Urban Nicole
Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
PLoS One. 2007 Dec 5;2(12):e1281. doi: 10.1371/journal.pone.0001281.
Evaluating diagnostic and early detection biomarkers requires comparing serum protein concentrations among biosamples ascertained from subjects with and without cancer. Efforts are generally made to standardize blood processing and storage conditions for cases and controls, but blood sample collection conditions cannot be completely controlled. For example, blood samples from cases are often obtained from persons aware of their diagnoses, and collected after fasting or in surgery, whereas blood samples from some controls may be obtained in different conditions, such as a clinic visit. By measuring the effects of differences in collection conditions on three different markers, we investigated the potential of these effects to bias validation studies.
We analyzed serum concentrations of three previously studied putative ovarian cancer serum biomarkers-CA 125, Prolactin and MIF-in healthy women, women with ovarian cancer undergoing gynecologic surgery, women undergoing surgery for benign ovary pathology, and women undergoing surgery with pathologically normal ovaries. For women undergoing surgery, a blood sample was collected either in the clinic 1 to 39 days prior to surgery, or on the day of surgery after anesthesia was administered but prior to the surgical procedure, or both. We found that one marker, prolactin, was dramatically affected by collection conditions, while CA 125 and MIF were unaffected. Prolactin levels were not different between case and control groups after accounting for the conditions of sample collection, suggesting that sample ascertainment could explain some or all of the previously reported results about its potential as a biomarker for ovarian cancer.
Biomarker validation studies should use standardized collection conditions, use multiple control groups, and/or collect samples from cases prior to influence of diagnosis whenever feasible to detect and correct for potential biases associated with sample collection.
评估诊断和早期检测生物标志物需要比较从患癌和未患癌受试者获取的生物样本中的血清蛋白浓度。人们通常努力使病例组和对照组的血液处理及储存条件标准化，但血液样本的采集条件无法完全控制。例如，病例组的血液样本通常来自知晓自己诊断结果的人，在禁食后或手术中采集，而一些对照组的血液样本可能在不同条件下采集，如门诊就诊时。通过测量采集条件差异对三种不同标志物的影响，我们研究了这些影响使验证研究产生偏差的可能性。
我们分析了三种先前研究过的假定卵巢癌血清生物标志物——CA 125、催乳素和巨噬细胞移动抑制因子（MIF）——在健康女性、接受妇科手术的卵巢癌女性、因良性卵巢病变接受手术的女性以及卵巢病理正常接受手术的女性中的血清浓度。对于接受手术的女性，在手术前1至39天于诊所采集血液样本，或在麻醉后但手术前的手术当天采集，或两者都采集。我们发现，一种标志物催乳素受采集条件的影响很大，而CA 125和MIF不受影响。在考虑样本采集条件后，病例组和对照组的催乳素水平没有差异，这表明样本确定可能解释了先前报道的关于其作为卵巢癌生物标志物潜力的部分或全部结果。
生物标志物验证研究应使用标准化的采集条件，使用多个对照组，和/或在可行的情况下，在诊断影响之前从病例中采集样本，以检测和纠正与样本采集相关的潜在偏差。
