(23.8%) were involved in responses to dif- ferent stimuli in particular immune responses (e.g., immunoglobulins, signal transduction proteins, and elements of the complement sys- tem). Furthermore, a large number of proteins were involved in cellular (13.7%), regulatory biological (13.3%), and metabolic processes (11.8%). Several of these proteins are known to be actively secreted into the bloodstream— for example, to maintain homeostasis in the body. An example is angiotensinogen, which is part of the renin–angiotensin system and regulates blood pressure. An interesting cat- egory, especially with respect to child devel- opment, is the GO class of multicellular organismal development, describing several critical proteins involved in embryonic skel- etal/bone system development essential for fetal growth (see Appendix 3, Hansmeier et al. 2012). About 8.6% of identified proteins belonged to this group, including homeobox protein DLX-6 (P56179), sickle tail protein homolog (Q5T5P2), and fetuin-A (P02765) (Graham 2002; Karamessinis et al. 2008; Semba et al. 2006). Although these proteins are not necessarily specific to the UCB pro- teome, their importance for embryogenesis is well recognized. Moreover, we organized the UCB pro- teome into metabolic pathways according to the KEGG database to identify which cel- lular processes may be traced using UCB. A total of 138 metabolic and signaling path- ways were found to be active (Figure 3; see also Appendix 4, Hansmeier et al. 2012). This includes proteins involved in immune response pathways, in control of the circula- tory, endocrine, digestive, nervous systems, and in cellular metabolism and catabolism. Furthermore, traceable proteins belonged to a diverse range of signaling pathways in devel- opmental processes, for example, for calcium, 8.6% 23.8% 4.2% 4.5% 11.8% 6.1% 13.7% 6.4% 7.6% 13.3% Response to stimulus Cellular process Regulation of biological process Multicellular organismal process Cell communication Transport Nucleic acid metabolic process Cell death Metabolic process Multicellular organismal development Human umbilical cord blood proteome survey MAPK (mitogen-activated protein kinases), WNT (signaling pathway first discovered in Drosophila melanogaster), and Jak-STAT (Janus kinase-signal transducer and activa- tor of transcription). Moreover, 54 proteins were already assigned to known human disease pathways and might be relevant for tracking disease-related changes earlier in life associ- ated with maturity-onset diabetes of the young (MODY), primary immunodeficiency, sys- temic lupus erythematosus, ventricular/hyper- tonic or dilated cardiomyopathy, diverse kind of cancers, or infectious diseases. Finally, we identified proteins in UCB that already are approved as biomarkers in adults by the FDA [Supplemental Material, Table 2 (http://dx.doi.org/10.1289/ehp.1104190)], including 38 proteins diagnostic of a diverse range of disorders, for example, artery and organ diseases and inflammation in adults (Anderson 2010). Discussion The rising prevalence of newborn diseases with long-term effects (Bloomgarden 2004; Ferrara 2007), such as diabetes, obesity, and chronic heart and kidney diseases, is expected to usher in new methods of UCB screening for early diagnosis in neonates. The present data set represents an important step forward in char- acterizing the proteome UCB composition and detecting candidate biomarkers therein. The high-confidence UCB data set (≥ 99% confidence, 1% protein FDR) of the UCB proteome is comparable in size with the high- quality data set from Schenk et al. (2008). As expected, a significant portion (~ 25%) of the proteins detected in UCB was previously found in adult blood. Because only limited information is available regarding the concen- tration range of UCB proteins, we estimated the depth of our analysis from known adult blood protein levels. For instance, among identified targets were titin and mitochon- drial glycine amidinotransferase, two proteins known to occur in the low nanogram per mil- liliter range (4–6.8 ng/mL) in blood (Farrah et al. 2011). Assuming that proteins occur at comparable levels in adult and fetal blood (i.e., within an order of magnitude), our data likely covered a dynamic range of about six to seven orders of magnitude, which is in line with prior reports on adult blood (e.g., Chan et al. 2004). No. of identiﬁed proteins 70 60 50 40 100 90 80 30 20 10 0 s m e t s y s l a m s i n a g r O l tena tion ing m a ss on rm ec irvn ifno rpo E anuHm issseaed m s i l o b a t e M tiec tianom issecgn enG firon rpo ra sse lllu se eC ropc Metabolic pathways Nucleotide metabolism Carbohydrate metabolism Amino acid metabolism Energy metabolism Lipid metabolism Glycan biosynthesis and metabolism Metabolism of cofactors and vitamins Immune systems Circulatory system Digestive system Endocrine system Excretory system Nervous system Sensory system Development Environmental adaptation Folding, sorting, and degradation Replication and repair Translation Transcription Cell communication Cell motility Cell growth and death Transport and catabolism Signal transduction Signaling molecules and interaction Membrane transport Infectious diseases Metabolic diseases Immune system diseases Neurodegenerative diseases Cardiovascular diseases Cancers Figure 2. Classification of the UCB proteome according to GO. Figure 3. Overview of UCB proteins mapped to KEGG pathways. See Appendix 4 (Hansmeier 2012) for more detailed information. Environmental Health Perspectives • volume 120 | number 5 | May 2012 767