Biomarker variability

Mattsson N, Andreasson U, Persson S, Carrillo MC, Collins S, Chalbot S et al (2013) CSF biomarker variability in the Alzheimer s Association quality control program. Alzheimers Dement 9 251-261... 

Statistical studies of MALDI MS applied to bacterial samples show that some biomarker peaks are highly reproducible and appear very consistently, while others appear much less reliably.1719 In Jarman et al.20 and Wahl et al.21 a probability model for MALDI signatures is proposed that takes into account the variability in appearance of biomarker peaks. This method constructs MALDI reference signatures from the set of peak locations for reproducible biomarker peaks, along with a measure of the reproducibility of each peak. 

The interaction between exposure intensity and duration of exposure in the development of neurobehavioral deficits is not understood, in part because of a lack of biomarkers of long-term lead exposure. The strongest evidence for health effects of low level lead exposures on neurodevelopmental deficits is based on relationships between measured health outcomes and PbB concentrations. Although these studies suggest that a significant amount of the variability in the health outcomes (e.g., neurobehavioral deficits) can be attributed to variability in PbB concentrations, a substantial amount of variability in the outcomes usually cannot be assigned to PbB, even after many known potential confounders have been considered (i.e., Needleman and Gatsonis 1990 Pocock et al. 1994 Schwartz 1994 Winneke 1996). 

While hemoglobin adduct formation does not imply altered or abnormal hemoglobin function, adduct formation may be a suitable biomarker of human exposure to 3,3 -dichlorobenzidine (see Section 2.7). Hematological variables (erythrocyte count, hemoglobin concentration, hematocrit, and leucocyte count) were found to be normal in dogs exposed to 10.4 mg/kg/day 3,3 -dichlorobenzidine for 7 years (Stula et al. 1978). 

It is well recognised that the faecal bile acid content of random stool samples is highly variable with marked daily variation.Therefore, studies testing the association between luminal bile acid exposure and the presence of colorectal neoplasia have usually measured serum bile acid levels, which demonstrate less variability and are believed to reflect the total bile acid pool more accurately. Serum DCA levels have been shown to be higher in individuals with a colorectal adenoma compared with individuals without a neoplasm. Only one study has assessed future risk of CRC in a prospective study of serum bile-acid levels. The study was hampered by the small sample size (46 CRC cases). There were no significant differences in the absolute concentrations of primary and secondary bile acids or DCA/CA ratio between cases and controls although there was a trend towards increased CRC risk for those with a DCA/ CA ratio in the top third of values (relative risk 3.9 [95% confidence interval 0.9-17.0 = 0.1]). It will be important to test the possible utility of the DCA/ CA ratio as a CRC risk biomarker in larger, adequately powered studies. A recent study has demonstrated increased levels of allo-DCA and allo-LCA metabolites in the stool of CRC patients compared with healthy controls. ... 

High-throughput assay of bile acids is technically demanding and expensive. Combined with high intra- and inter-individual variability in stool bile acid levels, it is unlikely that bile acid measurement will find a role as a biomarker of future colorectal neoplastic risk. 

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT >3x ULN), cholestatic (ALP >2x ULN, ALT/ALP <2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

The concentration of fluoride in nails and hair appears to be proportional to intake over longer periods of time, taking into account their growth rate [100-103]. Exposure to fluoride may occur in the local environment at the place of residence or via occupational exposure. Daily intake from food, water, dentifrices or fluoride supplements also contributes. The major advantage of nails and hair over fluids and tissues as biomarkers for fluoride exposure is that they can easily be obtained in a non-invasive manner. In contrast to plasma, saliva and urine, whose fluoride concentrations provide a snapshot at a certain point of time and are subject to change due to recent fluoride intake and certain physiological variables, the concentration of fluoride in nails and hair is cumulative and reflects the average level of intake over a time period, but depends on how often the nails are clipped or hair cut. 

To ensure lot-to-lot consistency, standardization of extracts often relies on constituents as biomarkers for plant identity and potency. SJW Hypericum perforatum), a perennial shrub traditionally used as a mood enhancer and mild antidepressant, has been tested in dozens of clinical trials, with mixed results for efficacy. Some of its purported bioactive constituents include naphthodianthrones, including hypericin flavonoids phloroglucinols, including hyperforin and essential oils. For many years, hypericin was presumed to be the active component. As a result most extracts were standardized based on hypericin concentration. Recent data, however, support other components such as hyperforin and the flavanoids, that may also contribute to the therapeutic efficacy of the SJW extracts (33-35). Because these secondary components were previously unaccounted for in the standardization of the former clinical test articles, and because these constituents are chemically unrelated to and their content within the plant varies independently of hypericin, it has been argued that the potency of these constituents in any particular batch was unlikely to be similar to that of other batches. This variability between batches could explain the observed differences in the clinical trial results (36). 

Cerda, B., Tomas-Barberan, F. A., and Espin, J. C. (2005) Metabolism of antioxidant and chemo-preventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans Identification of biomarkers and individual variability, J. Agric. Food Chem. 53 227-235. 

---