%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Krista E. van Meijgaarden, Bhagwati Khatri, Steven G. Smith, Anne M. F. H. Drittij, Roelof A. de Paus, Jelle J. Goeman, Mei M. Ho, Hazel M. Dockrell, Helen McShane, Simone A. Joosten, Tom H. M. Ottenhoff
Cross-laboratory evaluation of multiplex bead assays including independent common reference standards for immunological monitoring of observational and interventional human studies
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 13 0 R/Contents 14 0 R/TrimBox[0 0 612 792]>>
endobj
13 0 obj
[15 0 R 16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R]
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref001)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref002)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref003)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref004)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref005)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref008)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref009)>>
endobj
22 0 obj
<>/Border[0 0 0]/A 23 0 R>>
endobj
23 0 obj
<>
endobj
14 0 obj
[24 0 R 25 0 R 26 0 R 27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R]
endobj
24 0 obj
<>stream
q
0.45 0.36 0.35 0.01 k
0 w
575.9997 591.91 m
199.9998 591.91 l
199.9998 592.41 l
575.9997 592.41 l
f*
0.83 0.64 0.02 0 k
436.3087 393.9024 m
441.0709 393.9024 l
h
f*
548.2205 354.8976 m
552.9827 354.8976 l
h
f*
277.6819 185.8961 m
282.3874 185.8961 l
h
f*
286.8661 185.8961 m
291.6283 185.8961 l
h
f*
522.4252 159.9307 m
527.1874 159.9307 l
h
f*
532.3465 159.9307 m
537.1087 159.9307 l
h
f*
280.2331 133.9087 m
284.9953 133.9087 l
h
f*
0 g
1 j
1 J
11.4998 0 0 11.4998 200.0125 706.3937 cm
BT
/F2 1 Tf
1 TL
-0.0035 Tc
0 0 Td
(Conclusions)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 200.0125 689.3858 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(We)Tj
1.7127 0 Td
(strongly)Tj
3.682 0 Td
(recommend)Tj
5.4485 0 Td
(using)Tj
2.578 0 Td
(multiplex)Tj
4.1177 0 Td
(assays)Tj
3.3001 0 Td
(from)Tj
2.208 0 Td
(the)Tj
1.5934 0 Td
(same)Tj
2.6437 0 Td
(manufactu)Tj
4.6309 0 Td
(rer)Tj
1.4262 0 Td
(within)Tj
2.7392 0 Td
(a)Tj
0.7698 0 Td
(single)Tj
-36.8502 -1.474 Td
(study)Tj
2.5839 0 Td
(and)Tj
1.862 0 Td
(across)Tj
3.133 0 Td
(studies)Tj
3.3478 0 Td
(that)Tj
1.8679 0 Td
(are)Tj
1.6471 0 Td
(likely)Tj
2.399 0 Td
(to)Tj
1.0443 0 Td
(compare)Tj
4.07 0 Td
(results)Tj
3.127 0 Td
(in)Tj
0.9787 0 Td
(a)Tj
0.7698 0 Td
(quantitative)Tj
5.2635 0 Td
(manner.)Tj
3.8491 0 Td
(Incorpo-)Tj
-35.9431 -1.468 Td
(ration)Tj
2.6854 0 Td
(of)Tj
1.0503 0 Td
(common)Tj
4.0222 0 Td
(reference)Tj
4.3982 0 Td
(standards,)Tj
4.8397 0 Td
(and)Tj
1.8679 0 Td
(application)Tj
4.9293 0 Td
(of)Tj
1.0443 0 Td
(the)Tj
1.5934 0 Td
(same)Tj
2.6496 0 Td
(analysis)Tj
3.7835 0 Td
(method)Tj
3.5209 0 Td
(in)Tj
-36.3847 -1.474 Td
(assays)Tj
3.3001 0 Td
(can)Tj
1.8141 0 Td
(overcome)Tj
4.5713 0 Td
(many)Tj
2.6436 0 Td
(analytical)Tj
4.3325 0 Td
(biases)Tj
3.0734 0 Td
(and)Tj
1.8619 0 Td
(thus)Tj
2.0946 0 Td
(could)Tj
2.5781 0 Td
(bridge)Tj
2.9599 0 Td
(comparison)Tj
5.3291 0 Td
(of)Tj
1.0444 0 Td
(indepen-)Tj
-35.603 -1.474 Td
(dent)Tj
2.1423 0 Td
(immune)Tj
3.7418 0 Td
(profiling)Tj
3.6641 0 Td
(\(e.g.)Tj
2.2021 0 Td
(vaccine)Tj
3.5746 0 Td
(immunogenicity\))Tj
7.4178 0 Td
(studies.)Tj
3.6283 0 Td
(With)Tj
2.2081 0 Td
(these)Tj
2.6377 0 Td
(recommendation)Tj
7.37 0 Td
(s)Tj
-38.5868 -1.474 Td
(taken)Tj
2.6377 0 Td
(into)Tj
1.8082 0 Td
(account,)Tj
3.9684 0 Td
(the)Tj
1.5934 0 Td
(multiplex)Tj
4.1117 0 Td
(bead)Tj
2.4169 0 Td
(assays)Tj
3.3061 0 Td
(performed)Tj
4.7264 0 Td
(as)Tj
1.2651 0 Td
(described)Tj
4.5056 0 Td
(here)Tj
2.1961 0 Td
(are)Tj
1.6471 0 Td
(useful)Tj
2.8525 0 Td
(tools)Tj
-37.0352 -1.474 Td
(in)Tj
0.9846 0 Td
(capturing)Tj
4.2788 0 Td
(complex)Tj
3.9029 0 Td
(human)Tj
3.2464 0 Td
(immune-signa)Tj
6.2123 0 Td
(tures)Tj
2.4169 0 Td
(in)Tj
0.9847 0 Td
(observational)Tj
6.0929 0 Td
(and)Tj
1.8679 0 Td
(interventional)Tj
6.087 0 Td
(studies.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 541.9842 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 524.9763 cm
BT
/F6 1 Tf
1 TL
-0.02 Tc
0 0 Td
(Multiplex)Tj
3.9571 0 Td
(bead)Tj
2.0523 0 Td
(assays)Tj
2.5284 0 Td
(are)Tj
1.4004 0 Td
(commonly)Tj
4.4163 0 Td
(used)Tj
1.9956 0 Td
(for)Tj
1.3379 0 Td
(monitoring)Tj
4.6602 0 Td
(of)Tj
0.9864 0 Td
(complex)Tj
3.5093 0 Td
(multicomponent)Tj
6.7464 0 Td
(signatures)Tj
-33.5903 -1.2982 Td
(of)Tj
0.9807 0 Td
(human)Tj
2.9991 0 Td
(immune)Tj
3.5319 0 Td
(responses)Tj
3.9458 0 Td
(in)Tj
1.0035 0 Td
(observational)Tj
5.3744 0 Td
(as)Tj
0.9808 0 Td
(well)Tj
1.7575 0 Td
(as)Tj
0.9808 0 Td
(interventional)Tj
5.6352 0 Td
(studies,)Tj
3.0841 0 Td
(such)Tj
1.9956 0 Td
(as)Tj
0.9807 0 Td
(treatment)Tj
-33.2501 -1.2983 Td
(or)Tj
1.0658 0 Td
(vaccination)Tj
4.6488 0 Td
(trials.)Tj
2.313 0 Td
(Measurement)Tj
5.5672 0 Td
(of)Tj
0.9808 0 Td
(secreted)Tj
3.3449 0 Td
(inflammatory)Tj
5.5162 0 Td
(mediators)Tj
4.0875 0 Td
(is)Tj
0.8164 0 Td
(relevant)Tj
3.2938 0 Td
(to)Tj
0.9921 0 Td
(many)Tj
2.4151 0 Td
(fields)Tj
-35.0416 -1.3039 Td
(of)Tj
0.9807 0 Td
(study,)Tj
2.5172 0 Td
(including)Tj
3.9004 0 Td
(human)Tj
2.9991 0 Td
(infectious)Tj
3.9684 0 Td
(diseases,)Tj
3.464 0 Td
(autoimmune)Tj
5.2327 0 Td
(diseases,)Tj
3.4582 0 Td
(cell)Tj
1.4967 0 Td
(signaling,)Tj
3.8891 0 Td
(neuroscience,)Tj
-31.9065 -1.2983 Td
(cardiovascular)Tj
5.7769 0 Td
(diseases)Tj
3.2542 0 Td
(and)Tj
1.6781 0 Td
(cancer.)Tj
2.9593 0 Td
(In)Tj
1.0772 0 Td
(addition,)Tj
3.6793 0 Td
(more)Tj
2.2791 0 Td
(reagents)Tj
3.4129 0 Td
(and)Tj
1.6837 0 Td
(assays)Tj
2.5285 0 Td
(are)Tj
1.4003 0 Td
(becoming)Tj
4.0535 0 Td
(available)Tj
-33.783 -1.2982 Td
(for)Tj
1.3379 0 Td
(other)Tj
2.2677 0 Td
(species)Tj
2.8856 0 Td
(such)Tj
1.9956 0 Td
(as)Tj
0.9808 0 Td
(mice,)Tj
2.3017 0 Td
(porcines,)Tj
3.7191 0 Td
(canines,)Tj
3.3221 0 Td
(rats)Tj
1.6214 0 Td
(and)Tj
1.6838 0 Td
(non-human)Tj
4.8869 0 Td
(primates.)Tj
3.7927 0 Td
(These)Tj
2.4888 0 Td
(advances)Tj
-33.2841 -1.2983 Td
(will)Tj
1.5987 0 Td
(facilitate)Tj
3.4412 0 Td
(cross-species)Tj
5.159 0 Td
(comparisons)Tj
5.1647 0 Td
(of)Tj
0.9808 0 Td
(multicomponent)Tj
6.7521 0 Td
(immune)Tj
3.5263 0 Td
(signatures.)Tj
-0.004 Tc
-25.4266 -1.3039 Td
(There)Tj
2.5795 0 Td
(are)Tj
1.4513 0 Td
(many)Tj
2.4775 0 Td
(components)Tj
5.1703 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(host)Tj
1.9162 0 Td
(immune)Tj
3.6283 0 Td
(response)Tj
3.7304 0 Td
(that)Tj
1.7801 0 Td
(may)Tj
1.9276 0 Td
(contribute)Tj
4.3936 0 Td
(to)Tj
1.0262 0 Td
(these)Tj
2.2507 0 Td
(sig-)Tj
-36.0111 -1.2983 Td
(natures,)Tj
3.4072 0 Td
(including)Tj
4.0422 0 Td
(T-cells,)Tj
3.1067 0 Td
(B-cells,)Tj
3.0784 0 Td
(NK)Tj
1.6271 0 Td
(cells,)Tj
2.1486 0 Td
(neutrophils)Tj
4.8132 0 Td
(and)Tj
1.7348 0 Td
(monocytes.)Tj
4.7849 0 Td
(Multiple)Tj
3.6396 0 Td
(cytokines)Tj
-32.3827 -1.2982 Td
(and)Tj
1.7291 0 Td
(chemokines)Tj
5.0173 0 Td
(can)Tj
1.627 0 Td
(be)Tj
1.1509 0 Td
(produced)Tj
4.0422 0 Td
(simultaneously)Tj
6.2475 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(magnitude)Tj
4.5297 0 Td
(and)Tj
1.7348 0 Td
(balance)Tj
3.2371 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2507 0 Td
(dif-)Tj
-35.7786 -1.304 Td
(ferent)Tj
2.5738 0 Td
(mediators)Tj
4.2293 0 Td
(defines)Tj
3.0557 0 Td
(the)Tj
1.474 0 Td
(functional)Tj
4.3086 0 Td
(response)Tj
3.7304 0 Td
(signature)Tj
3.9175 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(]].)Tj
1.9388 0 Td
(Over)Tj
2.2167 0 Td
(the)Tj
1.474 0 Td
(last)Tj
1.5591 0 Td
(decade)Tj
2.9763 0 Td
(various)Tj
-33.4542 -1.2982 Td
(commercially)Tj
5.6579 0 Td
(available)Tj
3.6623 0 Td
(multiplex)Tj
4.0308 0 Td
(suspension)Tj
4.6432 0 Td
(bead)Tj
2.1146 0 Td
(assays)Tj
2.6249 0 Td
(have)Tj
2.0579 0 Td
(been)Tj
2.126 0 Td
(developed)Tj
4.2689 0 Td
(and)Tj
1.7291 0 Td
(gradually)Tj
-32.9156 -1.2983 Td
(improved)Tj
4.1045 0 Td
(towards)Tj
3.4072 0 Td
(more)Tj
2.3414 0 Td
(robust)Tj
2.7893 0 Td
(and)Tj
1.7291 0 Td
(user-)Tj
2.2564 0 Td
(friendly)Tj
3.3505 0 Td
(assays.)Tj
2.846 0 Td
(For)Tj
1.627 0 Td
(example,)Tj
3.7758 0 Td
(polystyrene)Tj
4.8245 0 Td
(beads)Tj
2.4718 0 Td
(have)Tj
-35.5235 -1.3039 Td
(been)Tj
2.1203 0 Td
(replaced)Tj
3.5886 0 Td
(with)Tj
1.9956 0 Td
(magnetic)Tj
3.9004 0 Td
(beads)Tj
2.4718 0 Td
(resulting)Tj
3.7304 0 Td
(in)Tj
1.0375 0 Td
(increased)Tj
3.9968 0 Td
(accuracy)Tj
3.7133 0 Td
(and)Tj
1.7292 0 Td
(reproducibility)Tj
6.1965 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(]].)Tj
-34.4804 -1.2983 Td
(The)Tj
1.7688 0 Td
(number)Tj
3.4128 0 Td
(of)Tj
1.0035 0 Td
(available)Tj
3.6567 0 Td
(analytes)Tj
3.4072 0 Td
(in)Tj
1.0261 0 Td
(a)Tj
0.6463 0 Td
(single)Tj
2.5228 0 Td
(assay)Tj
2.2507 0 Td
(has)Tj
1.5364 0 Td
(been)Tj
2.109 0 Td
(expanded)Tj
4.0762 0 Td
(to)Tj
1.0148 0 Td
(approximately)Tj
5.9697 0 Td
(40)Tj
1.1622 0 Td
(cyto-)Tj
-35.5632 -1.2982 Td
(kines)Tj
2.313 0 Td
(or)Tj
1.0998 0 Td
(chemokines.)Tj
5.2441 0 Td
(Because)Tj
3.3902 0 Td
(the)Tj
1.474 0 Td
(demand)Tj
3.498 0 Td
(for)Tj
1.3889 0 Td
(easy)Tj
1.8936 0 Td
(and)Tj
1.7291 0 Td
(robust)Tj
2.7893 0 Td
(multi-parameter)Tj
6.8257 0 Td
(assays)Tj
2.6249 0 Td
(is)Tj
0.8504 0 Td
(still)Tj
-35.121 -1.2983 Td
(increasing)Tj
4.3313 0 Td
(multiple)Tj
3.5659 0 Td
(vendors)Tj
3.4129 0 Td
(have)Tj
2.058 0 Td
(started)Tj
2.9366 0 Td
(to)Tj
1.0205 0 Td
(produce)Tj
3.5206 0 Td
(and)Tj
1.7291 0 Td
(market)Tj
3.0671 0 Td
(these)Tj
2.2507 0 Td
(assays.)Tj
2.8516 0 Td
(In)Tj
1.1112 0 Td
(human)Tj
3.0727 0 Td
(vacci-)Tj
-34.9282 -1.3039 Td
(nation)Tj
2.8232 0 Td
(studies,)Tj
3.2088 0 Td
(sample)Tj
3.0218 0 Td
(numbers)Tj
3.7813 0 Td
(and)Tj
1.7292 0 Td
(volumes)Tj
3.5603 0 Td
(are)Tj
1.4456 0 Td
(often)Tj
2.2904 0 Td
(limited,)Tj
3.2938 0 Td
(in)Tj
1.0375 0 Td
(particular)Tj
4.1102 0 Td
(when)Tj
2.4038 0 Td
(involving)Tj
-32.7059 -1.2983 Td
(young)Tj
2.7212 0 Td
(children,)Tj
3.7814 0 Td
(and)Tj
1.7291 0 Td
(frequently)Tj
4.3086 0 Td
(involve)Tj
3.1238 0 Td
(longitudinal)Tj
5.1023 0 Td
(sampling)Tj
3.8778 0 Td
(such)Tj
2.0636 0 Td
(that)Tj
1.7802 0 Td
(assays)Tj
2.6248 0 Td
(are)Tj
1.4457 0 Td
(preferred)Tj
-32.5585 -1.2982 Td
(that)Tj
1.7744 0 Td
(are)Tj
1.4514 0 Td
(high-throughput,)Tj
7.1546 0 Td
(able)Tj
1.8255 0 Td
(to)Tj
1.0261 0 Td
(handle)Tj
2.931 0 Td
(small)Tj
2.3244 0 Td
(sample)Tj
3.0217 0 Td
(volumes)Tj
3.5603 0 Td
(and)Tj
1.7291 0 Td
(still)Tj
1.6384 0 Td
(provide)Tj
3.2882 0 Td
(multi-factorial)Tj
-31.7251 -1.304 Td
(signature)Tj
3.9174 0 Td
(data.)Tj
2.1373 0 Td
(Current)Tj
3.4242 0 Td
(commercial)Tj
4.955 0 Td
(multiplex)Tj
4.0308 0 Td
(bead)Tj
2.1146 0 Td
(assays)Tj
2.6249 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1508 0 Td
(performed)Tj
4.4674 0 Td
(on)Tj
1.2756 0 Td
(as)Tj
1.0148 0 Td
(little)Tj
2.0012 0 Td
(as)Tj
1.0148 0 Td
(25)Tj
-35.7559 -1.2982 Td
(50)Tj
/F11 1 Tf
1.1678 0 Td
[()]TJ
/F6 1 Tf
(l)Tj
0.9751 0 Td
(of)Tj
1.0148 0 Td
(culture)Tj
3.0387 0 Td
(supernatant)Tj
4.9833 0 Td
(from)Tj
2.2054 0 Td
(stimulated)Tj
4.422 0 Td
(PBMC)Tj
2.914 0 Td
(cultures,)Tj
3.6283 0 Td
(\(diluted\))Tj
3.719 0 Td
(venous)Tj
3.0388 0 Td
(blood)Tj
2.5171 0 Td
(or)Tj
1.0998 0 Td
(serum/)Tj
-34.7241 -1.2983 Td
(plasma,)Tj
3.2541 0 Td
(and)Tj
1.7348 0 Td
(enable)Tj
2.8006 0 Td
(analysis)Tj
3.3279 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(large)Tj
2.16 0 Td
(number)Tj
3.4186 0 Td
(of)Tj
1.0148 0 Td
(analytes.)Tj
3.6453 0 Td
(Another)Tj
3.583 0 Td
(major)Tj
2.6078 0 Td
(advantage)Tj
4.2406 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
-34.469 -1.3039 Td
(assays)Tj
2.6248 0 Td
(is)Tj
0.8447 0 Td
(that)Tj
1.7802 0 Td
(samples)Tj
3.3845 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1509 0 Td
(collected)Tj
3.736 0 Td
(and)Tj
1.7291 0 Td
(stored,)Tj
2.9367 0 Td
(thus)Tj
1.9332 0 Td
(allowing)Tj
3.617 0 Td
(serial)Tj
2.3244 0 Td
(measurements)Tj
6.0321 0 Td
(of)Tj
1.0148 0 Td
(sam-)Tj
-34.7355 -1.2983 Td
(ples)Tj
1.7688 0 Td
(from)Tj
2.2053 0 Td
(individuals)Tj
4.6488 0 Td
(in)Tj
1.0318 0 Td
(a)Tj
0.6576 0 Td
(single)Tj
2.5285 0 Td
(assay,)Tj
2.4945 0 Td
(thereby)Tj
3.2258 0 Td
(limiting)Tj
3.3959 0 Td
(inter-assay)Tj
4.524 0 Td
(variation)Tj
3.8041 0 Td
(and)Tj
1.7291 0 Td
(thus)Tj
1.9333 0 Td
(optimis-)Tj
-33.9475 -1.2982 Td
(ing)Tj
1.5023 0 Td
(detection)Tj
3.9345 0 Td
(of)Tj
1.0148 0 Td
(possibly)Tj
3.4412 0 Td
(subtle)Tj
2.5852 0 Td
(perturbations)Tj
5.6522 0 Td
(in)Tj
1.0318 0 Td
(cytokines,)Tj
4.2293 0 Td
(chemokines)Tj
5.0173 0 Td
(and)Tj
1.7291 0 Td
(other)Tj
2.3471 0 Td
(secreted)Tj
-32.4848 -1.304 Td
(analytes)Tj
3.4185 0 Td
(over)Tj
1.9786 0 Td
(time)Tj
2.0296 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2585 0 Td
(4)Tj
0 g
(].)Tj
1.2586 0 Td
(In)Tj
1.1112 0 Td
(the)Tj
1.4683 0 Td
(past)Tj
1.8312 0 Td
(few)Tj
1.6157 0 Td
(years)Tj
2.2621 0 Td
(many)Tj
2.4774 0 Td
(studies)Tj
2.9877 0 Td
(have)Tj
2.0636 0 Td
(been)Tj
2.1203 0 Td
(performed)Tj
4.4674 0 Td
(in)Tj
1.0375 0 Td
(which)Tj
-33.3862 -1.2982 Td
(multiplex)Tj
4.0308 0 Td
(assays)Tj
2.6249 0 Td
(were)Tj
2.1203 0 Td
(tested)Tj
2.5568 0 Td
(for)Tj
1.3833 0 Td
(accuracy)Tj
3.7134 0 Td
(and)Tj
1.7291 0 Td
(reproducibility)Tj
6.1965 0 Td
(by)Tj
1.1848 0 Td
(including)Tj
4.0422 0 Td
(spiked)Tj
2.812 0 Td
(samples)Tj
3.3789 0 Td
(or)Tj
-35.773 -1.2983 Td
(WHO)Tj
2.6985 0 Td
(standards,)Tj
4.3086 0 Td
(and)Tj
1.7292 0 Td
(compared)Tj
4.2462 0 Td
(to)Tj
1.0262 0 Td
(single)Tj
2.5285 0 Td
(analyte)Tj
3.0614 0 Td
(assays)Tj
2.6248 0 Td
(like)Tj
1.6555 0 Td
(ELISA)Tj
2.8232 0 Td
(and)Tj
1.7348 0 Td
(ELISpot)Tj
3.464 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
2.5908 0 Td
(More-)Tj
-34.4917 -1.2982 Td
(over)Tj
1.9729 0 Td
(their)Tj
2.1089 0 Td
(performance)Tj
5.3518 0 Td
(was)Tj
1.6951 0 Td
(evaluated)Tj
3.9912 0 Td
(in)Tj
1.0374 0 Td
(combination)Tj
5.3461 0 Td
(with)Tj
1.9956 0 Td
(optimized)Tj
4.2633 0 Td
(stimulation)Tj
4.7962 0 Td
(protocols)Tj
-32.5585 -1.304 Td
(for)Tj
1.3832 0 Td
(PBMC)Tj
2.914 0 Td
(samples)Tj
3.3846 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
1.6044 0 Td
(Even)Tj
2.211 0 Td
(though)Tj
3.0784 0 Td
(multiplex)Tj
4.0308 0 Td
(bead)Tj
2.109 0 Td
(assays)Tj
2.6249 0 Td
(cannot)Tj
2.982 0 Td
(identify)Tj
3.2938 0 Td
(the)Tj
1.4684 0 Td
(cellular)Tj
3.1407 0 Td
(source)Tj
-34.2252 -1.2982 Td
(of)Tj
1.0147 0 Td
(any)Tj
1.6555 0 Td
(biomarker)Tj
4.4163 0 Td
(measured)Tj
4.1102 0 Td
(but)Tj
1.5534 0 Td
(the)Tj
1.4683 0 Td
(total)Tj
2.007 0 Td
(concentration)Tj
5.8166 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(cytokine)Tj
3.6396 0 Td
(or)Tj
1.0999 0 Td
(chemokine)Tj
4.6544 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.652 0 Td
(given)Tj
-34.7922 -1.2983 Td
(sample,)Tj
3.2484 0 Td
(they)Tj
1.9219 0 Td
(provide)Tj
3.2882 0 Td
(powerful)Tj
3.787 0 Td
(tools)Tj
2.1374 0 Td
(for)Tj
1.3889 0 Td
(multicomponent)Tj
6.9675 0 Td
(analysis)Tj
3.3279 0 Td
(of)Tj
1.0148 0 Td
(immunologic)Tj
5.6182 0 Td
(responses,)Tj
-32.7002 -1.3039 Td
(which)Tj
2.6475 0 Td
(can)Tj
1.6271 0 Td
(guide)Tj
2.4321 0 Td
(further)Tj
3.0274 0 Td
(in-depth)Tj
3.6793 0 Td
(exploratory)Tj
4.8189 0 Td
(research)Tj
3.5546 0 Td
(to)Tj
1.0261 0 Td
(define)Tj
2.6986 0 Td
(the)Tj
1.4683 0 Td
(potential)Tj
3.7588 0 Td
(cellular)Tj
3.1407 0 Td
(sources)Tj
-33.8794 -1.2983 Td
(and)Tj
1.7291 0 Td
(cellular)Tj
3.1407 0 Td
(interactions)Tj
4.9663 0 Td
(involved.)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 360 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Multiplex)Tj
4.089 0 Td
(bead)Tj
2.4023 0 Td
(arrays)Tj
2.9481 0 Td
(benefit)Tj
3.1677 0 Td
(from)Tj
2.1969 0 Td
(commo)Tj
3.2315 0 Td
(n)Tj
0.7654 0 Td
(reference)Tj
4.3725 0 Td
(standard)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.02012)Tj
4.089 0 Td
(05)Tj
0 g
2.0906 0 Td
(September)Tj
5.0386 0 Td
(4,)Tj
1.0418 0 Td
(2018)Tj
32.8254 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(17)Tj
/F9 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(necessaril)Tj
3.6921 0 Td
(y)Tj
0.6449 0 Td
(represent)Tj
3.7205 0 Td
(a)Tj
0.6449 0 Td
(position)Tj
3.1748 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(Commission)Tj
-14.1945 -1.3748 Td
(who)Tj
1.8071 0 Td
(will)Tj
1.4385 0 Td
(not)Tj
1.4245 0 Td
(be)Tj
1.1126 0 Td
(liable)Tj
2.1118 0 Td
(for)Tj
1.2614 0 Td
(the)Tj
1.3678 0 Td
(use)Tj
1.5378 0 Td
(made)Tj
2.289 0 Td
(of)Tj
0.9496 0 Td
(such)Tj
-15.3001 -1.3749 Td
(information.)Tj
4.7197 0 Td
(The)Tj
1.5874 0 Td
(funders)Tj
3.0473 0 Td
(had)Tj
1.5874 0 Td
(no)Tj
1.1622 0 Td
(role)Tj
1.6157 0 Td
(in)Tj
0.8859 0 Td
(study)Tj
-14.6056 -1.3748 Td
(design,)Tj
2.8984 0 Td
(data)Tj
1.7929 0 Td
(collection)Tj
3.7418 0 Td
(and)Tj
1.5874 0 Td
(analysis,)Tj
3.4087 0 Td
(decision)Tj
3.2953 0 Td
(to)Tj
-16.7245 -1.3748 Td
(publish,)Tj
3.1464 0 Td
(or)Tj
0.9993 0 Td
(preparation)Tj
4.4433 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(manuscript.)Tj
/F8 1 Tf
-10.9063 -2.126 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F9 1 Tf
0.4819 0 Td
(The)Tj
1.5875 0 Td
(authors)Tj
3.0401 0 Td
(have)Tj
1.963 0 Td
(declared)Tj
-14.7827 -1.3748 Td
(that)Tj
1.6228 0 Td
(no)Tj
1.1693 0 Td
(competing)Tj
4.1599 0 Td
(interests)Tj
ET
endstream
endobj
25 0 obj
<>stream
endstream
endobj
26 0 obj
<>stream
endstream
endobj
27 0 obj
<>stream
endstream
endobj
28 0 obj
<>stream
endstream
endobj
29 0 obj
<>stream
endstream
endobj
30 0 obj
<>stream
endstream
endobj
31 0 obj
<>stream
endstream
endobj
32 0 obj
<>stream
BT
10.3394 75.0903 Td
(exist.)Tj
ET
Q
endstream
endobj
33 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 35 0 R/Contents 36 0 R/TrimBox[0 0 612 792]>>
endobj
35 0 obj
[37 0 R 38 0 R 39 0 R 40 0 R 41 0 R 42 0 R 43 0 R 44 0 R]
endobj
37 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref010)>>
endobj
38 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref011)>>
endobj
39 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.ref012)>>
endobj
40 0 obj
<>/Border[0 0 0]/A 45 0 R>>
endobj
45 0 obj
<>
endobj
41 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.g001)>>
endobj
42 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.g001)>>
endobj
43 0 obj
<>/Border[0 0 0]/Dest(Rpone.0201205.g001)>>
endobj
44 0 obj
<>/Border[0 0 0]/A 46 0 R>>
endobj
46 0 obj
<>
endobj
36 0 obj
[47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R 53 0 R]
endobj
47 0 obj
<>stream
q
0.83 0.64 0.02 0 k
326.0409 628.3276 m
335.5654 628.3276 l
h
f*
418.7339 602.3055 m
428.2583 602.3055 l
h
f*
432.6803 602.3055 m
442.2047 602.3055 l
h
f*
379.6157 237.9402 m
461.7071 237.9402 l
h
f*
494.4189 198.9354 m
520.8378 198.9354 l
h
f*
203.4142 159.9307 m
229.7764 159.9307 l
h
f*
282.0472 133.9087 m
308.4661 133.9087 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 211.9748 707.4141 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(For)Tj
1.627 0 Td
(each)Tj
2.0296 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(three)Tj
2.2677 0 Td
(major)Tj
2.6078 0 Td
(infectious)Tj
4.1329 0 Td
(diseases,)Tj
3.6 0 Td
(TB,)Tj
1.6384 0 Td
(HIV)Tj
2.0239 0 Td
(and)Tj
1.7291 0 Td
(malaria,)Tj
3.4526 0 Td
(human)Tj
3.0784 0 Td
(immune)Tj
-31.8668 -1.3039 Td
(responses)Tj
4.0931 0 Td
(induced)Tj
3.464 0 Td
(by)Tj
1.1848 0 Td
(vaccination,)Tj
5.0513 0 Td
(in)Tj
1.0318 0 Td
(particular)Tj
4.1159 0 Td
(new)Tj
1.8709 0 Td
(experimental)Tj
5.4595 0 Td
(vaccines)Tj
3.5546 0 Td
(under)Tj
2.6192 0 Td
(evaluation)Tj
-32.4451 -1.2982 Td
(are)Tj
1.4456 0 Td
(complex)Tj
3.6227 0 Td
(and)Tj
1.7291 0 Td
(multifactorial.)Tj
5.879 0 Td
(Therefore,)Tj
4.388 0 Td
(monitoring)Tj
4.8189 0 Td
(vaccine-induced)Tj
6.7917 0 Td
(changes)Tj
3.4073 0 Td
(over)Tj
1.9729 0 Td
(time)Tj
-34.0552 -1.2983 Td
(needs)Tj
2.5057 0 Td
(to)Tj
1.0205 0 Td
(be)Tj
1.1509 0 Td
(broad)Tj
2.5681 0 Td
(and)Tj
1.7292 0 Td
(include)Tj
3.1861 0 Td
(a)Tj
0.652 0 Td
(variety)Tj
2.9253 0 Td
(of)Tj
1.0148 0 Td
(cytokines)Tj
4.0025 0 Td
(and)Tj
1.7291 0 Td
(chemokines,)Tj
5.2441 0 Td
(rather)Tj
2.6418 0 Td
(than)Tj
2.0296 0 Td
(preselected)Tj
-32.3997 -1.2983 Td
(single)Tj
2.5284 0 Td
(markers.)Tj
3.7247 0 Td
(In)Tj
1.1112 0 Td
(malaria)Tj
3.2258 0 Td
(it)Tj
0.7824 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.126 0 Td
(shown)Tj
2.8459 0 Td
(that)Tj
1.7802 0 Td
(different)Tj
3.6567 0 Td
(stages)Tj
2.5625 0 Td
(of)Tj
1.0148 0 Td
(parasitic)Tj
3.5943 0 Td
(infection)Tj
3.787 0 Td
(involve)Tj
-34.2819 -1.3039 Td
(different)Tj
3.6566 0 Td
(cytokine)Tj
3.6397 0 Td
(patterns,)Tj
3.6963 0 Td
(and)Tj
1.7291 0 Td
(that)Tj
1.7802 0 Td
(the)Tj
1.4683 0 Td
(balance)Tj
3.2372 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(cytokines)Tj
4.0025 0 Td
(determines)Tj
4.6828 0 Td
(the)Tj
1.4683 0 Td
(control)Tj
3.1238 0 Td
(of)Tj
-34.9679 -1.2982 Td
(infection)Tj
3.7927 0 Td
(and)Tj
1.7291 0 Td
(disease)Tj
3.016 0 Td
(outcome)Tj
3.7247 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(].)Tj
2.0807 0 Td
(In)Tj
1.1055 0 Td
(BCG)Tj
2.1826 0 Td
(vaccination)Tj
4.8246 0 Td
(studies,)Tj
3.2088 0 Td
(complex)Tj
3.6226 0 Td
(cytokine)Tj
3.6397 0 Td
(profiles)Tj
-32.927 -1.2983 Td
(such)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(those)Tj
2.3357 0 Td
(obtained)Tj
3.736 0 Td
(by)Tj
1.1793 0 Td
(multiplex)Tj
4.0308 0 Td
(bead)Tj
2.1146 0 Td
(assays)Tj
2.6249 0 Td
(proved)Tj
3.0217 0 Td
(to)Tj
1.0261 0 Td
(be)Tj
1.1509 0 Td
(valuable)Tj
3.4923 0 Td
(tools)Tj
2.1373 0 Td
(to)Tj
1.0261 0 Td
(discriminate)Tj
-30.9484 -1.3039 Td
(vaccine)Tj
3.1917 0 Td
(induced)Tj
3.4696 0 Td
(responses)Tj
4.0932 0 Td
(across)Tj
2.6759 0 Td
(different)Tj
3.6567 0 Td
(continents)Tj
4.4447 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(12)Tj
0 g
(].)Tj
1.7404 0 Td
(For)Tj
1.6214 0 Td
(each)Tj
2.0296 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2564 0 Td
(three)Tj
2.262 0 Td
(diseases,)Tj
-34.1912 -1.2983 Td
(field)Tj
1.9728 0 Td
(studies)Tj
2.9821 0 Td
(and)Tj
1.7348 0 Td
(trials)Tj
2.194 0 Td
(are)Tj
1.4513 0 Td
(complicated)Tj
5.108 0 Td
(because)Tj
3.3165 0 Td
(of)Tj
1.0148 0 Td
(large)Tj
2.1657 0 Td
(group)Tj
2.6078 0 Td
(sizes,)Tj
2.2677 0 Td
(long)Tj
1.9899 0 Td
(follow-up)Tj
4.0932 0 Td
(times)Tj
2.3868 0 Td
(and)Tj
-35.2854 -1.2983 Td
(frequently)Tj
4.3086 0 Td
(poor)Tj
2.1203 0 Td
(local)Tj
2.0806 0 Td
(infrastructure)Tj
5.7316 0 Td
(in)Tj
1.0318 0 Td
(affected)Tj
3.3279 0 Td
(endemic)Tj
3.651 0 Td
(areas.)Tj
2.4718 0 Td
(In)Tj
1.1111 0 Td
(order)Tj
2.4208 0 Td
(to)Tj
1.0205 0 Td
(achieve)Tj
3.1748 0 Td
(sufficient)Tj
-32.4508 -1.3039 Td
(power,)Tj
2.9479 0 Td
(studies)Tj
2.9877 0 Td
(are)Tj
1.4457 0 Td
(frequently)Tj
4.3086 0 Td
(run)Tj
1.6668 0 Td
(at)Tj
0.9524 0 Td
(multiple)Tj
3.566 0 Td
(sites.)Tj
-16.6789 -1.2982 Td
(To)Tj
1.3379 0 Td
(search)Tj
2.7609 0 Td
(for)Tj
1.389 0 Td
(immune)Tj
3.6283 0 Td
(correlates)Tj
4.0762 0 Td
(of)Tj
1.0148 0 Td
(protection,)Tj
4.6091 0 Td
(it)Tj
0.7824 0 Td
(would)Tj
2.7155 0 Td
(be)Tj
1.1509 0 Td
(even)Tj
2.0693 0 Td
(more)Tj
2.3414 0 Td
(informative)Tj
4.8982 0 Td
(if)Tj
0.7767 0 Td
(it)Tj
0.7824 0 Td
(were)Tj
-35.5292 -1.2983 Td
(possible)Tj
3.4072 0 Td
(to)Tj
1.0261 0 Td
(perform)Tj
3.5206 0 Td
(head-to-head)Tj
5.5502 0 Td
(comparisons)Tj
5.3348 0 Td
(of)Tj
1.0148 0 Td
(responses)Tj
4.0988 0 Td
(induced)Tj
3.464 0 Td
(by)Tj
1.1792 0 Td
(different)Tj
3.6566 0 Td
(vaccine)Tj
3.1975 0 Td
(can-)Tj
-35.4498 -1.3039 Td
(didates)Tj
3.0557 0 Td
(in)Tj
1.0374 0 Td
(relation)Tj
3.3166 0 Td
(to)Tj
1.0261 0 Td
(clinical)Tj
3.0727 0 Td
(outcome,)Tj
3.9572 0 Td
(e.g.)Tj
1.559 0 Td
(protection)Tj
4.3823 0 Td
(or)Tj
1.0942 0 Td
(disease.)Tj
3.2428 0 Td
(At)Tj
1.2019 0 Td
(the)Tj
1.474 0 Td
(moment,)Tj
3.8608 0 Td
(the)Tj
1.4683 0 Td
(best)Tj
-33.749 -1.2983 Td
(proximate)Tj
4.3199 0 Td
(is)Tj
0.8504 0 Td
(to)Tj
1.0261 0 Td
(harmonize)Tj
4.5298 0 Td
(vaccine)Tj
3.1974 0 Td
(study)Tj
2.3868 0 Td
(design)Tj
2.8119 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8199 0 Td
(as)Tj
1.0148 0 Td
(immunological)Tj
6.3042 0 Td
(monitoring)Tj
4.8188 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
-35.121 -1.2982 Td
(highest)Tj
3.0897 0 Td
(degree)Tj
2.8516 0 Td
(possible.)Tj
3.6397 0 Td
(Harmonization)Tj
6.4006 0 Td
(of)Tj
1.0148 0 Td
(assays)Tj
2.6248 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(multiplex)Tj
4.0308 0 Td
(bead)Tj
2.109 0 Td
(assay)Tj
2.2677 0 Td
(would)Tj
2.7099 0 Td
(allow)Tj
-35.2854 -1.2983 Td
(an)Tj
1.2018 0 Td
(unique)Tj
3.0217 0 Td
(opportunity)Tj
5.0343 0 Td
(to)Tj
1.0262 0 Td
(conduct)Tj
3.4752 0 Td
(comparative)Tj
5.1704 0 Td
(analysis)Tj
3.3278 0 Td
(of)Tj
1.0148 0 Td
(vaccine)Tj
3.1918 0 Td
(induced)Tj
3.4696 0 Td
(immune)Tj
3.6227 0 Td
(responses)Tj
-33.5563 -1.3039 Td
(over)Tj
1.9728 0 Td
(sites)Tj
1.9333 0 Td
(and)Tj
1.7291 0 Td
(over)Tj
1.9785 0 Td
(different)Tj
3.6567 0 Td
(vaccination)Tj
4.8246 0 Td
(trials.)Tj
2.4207 0 Td
(However,)Tj
4.0819 0 Td
(to)Tj
1.0205 0 Td
(run)Tj
1.6724 0 Td
(harmonization)Tj
6.1625 0 Td
(optimally)Tj
4.0081 0 Td
(it)Tj
0.7881 0 Td
(is)Tj
-36.2492 -1.2983 Td
(critical)Tj
2.9479 0 Td
(to)Tj
1.0262 0 Td
(identify)Tj
3.2938 0 Td
(the)Tj
1.474 0 Td
(factors)Tj
2.9027 0 Td
(that)Tj
1.7745 0 Td
(are)Tj
1.4513 0 Td
(responsible)Tj
4.7508 0 Td
(for)Tj
1.389 0 Td
(variation)Tj
3.7984 0 Td
(within)Tj
2.8176 0 Td
(an)Tj
1.2019 0 Td
(assay.)Tj
2.4888 0 Td
(Therefore,)Tj
4.3937 0 Td
(we)Tj
-35.7106 -1.2983 Td
(have)Tj
2.0579 0 Td
(here)Tj
1.9672 0 Td
(conducted)Tj
4.4277 0 Td
(a)Tj
0.652 0 Td
(technical)Tj
3.8154 0 Td
(comparative)Tj
5.1703 0 Td
(study)Tj
2.3868 0 Td
(of)Tj
1.0148 0 Td
(multiplex)Tj
4.0308 0 Td
(cytokine)Tj
3.6397 0 Td
(and)Tj
1.7291 0 Td
(chemokine)Tj
-30.8917 -1.3039 Td
(assays)Tj
2.6248 0 Td
(between)Tj
3.5263 0 Td
(3)Tj
0.6973 0 Td
(laboratories,)Tj
5.1704 0 Td
(using)Tj
2.3924 0 Td
(the)Tj
1.4683 0 Td
(kits)Tj
1.6441 0 Td
(from)Tj
2.2053 0 Td
(4)Tj
0.6974 0 Td
(manufacturers)Tj
6.0491 0 Td
(and)Tj
1.7291 0 Td
(3)Tj
0.6973 0 Td
(different)Tj
3.651 0 Td
(lots,)Tj
1.8595 0 Td
(testing)Tj
-34.4123 -1.2982 Td
(the)Tj
1.4683 0 Td
(same)Tj
2.2563 0 Td
(samples,)Tj
3.6114 0 Td
(including)Tj
4.0421 0 Td
(spiked)Tj
2.812 0 Td
(samples,)Tj
3.6056 0 Td
(biological)Tj
4.0932 0 Td
(samples)Tj
3.3789 0 Td
(and)Tj
1.7291 0 Td
(a)Tj
0.6577 0 Td
(newly)Tj
2.5738 0 Td
(made)Tj
2.4264 0 Td
(reference)Tj
-32.6548 -1.2983 Td
(standard)Tj
3.719 0 Td
(as)Tj
1.0148 0 Td
(key)Tj
1.5987 0 Td
(reagents)Tj
3.5433 0 Td
(to)Tj
1.0261 0 Td
(understand)Tj
4.7905 0 Td
(the)Tj
1.4684 0 Td
(assay)Tj
2.262 0 Td
(variation)Tj
3.8041 0 Td
(and)Tj
1.7291 0 Td
(interdependence.)Tj
7.1433 0 Td
(We)Tj
1.61 0 Td
(then)Tj
-33.7093 -1.3039 Td
(determined)Tj
4.8472 0 Td
(the)Tj
1.474 0 Td
(major)Tj
2.6078 0 Td
(components)Tj
5.176 0 Td
(responsible)Tj
4.7509 0 Td
(for)Tj
1.3833 0 Td
(variation)Tj
3.8041 0 Td
(based)Tj
2.4717 0 Td
(on)Tj
1.2756 0 Td
(advanced)Tj
3.9969 0 Td
(unbiased)Tj
3.8154 0 Td
(sta-)Tj
-35.6029 -1.2983 Td
(tistical)Tj
2.8119 0 Td
(methods.)Tj
3.9118 0 Td
(The)Tj
1.7858 0 Td
(results)Tj
2.8063 0 Td
(described)Tj
4.0535 0 Td
(below)Tj
2.5852 0 Td
(provide)Tj
3.2881 0 Td
(recommendations)Tj
7.5005 0 Td
(for)Tj
1.3889 0 Td
(optimal)Tj
3.3109 0 Td
(use)Tj
1.5307 0 Td
(of)Tj
-34.9736 -1.2983 Td
(multiplex)Tj
4.0308 0 Td
(bead)Tj
2.1089 0 Td
(assays)Tj
2.6306 0 Td
(across)Tj
2.6759 0 Td
(different)Tj
3.6566 0 Td
(laboratories)Tj
4.9436 0 Td
(and)Tj
1.7348 0 Td
(studies.)Tj
-20.585 -1.2982 Td
(The)Tj
1.7858 0 Td
(EURIPRED)Tj
4.9719 0 Td
(consortium)Tj
4.8529 0 Td
(aimed)Tj
2.6929 0 Td
(to)Tj
1.0261 0 Td
(identify)Tj
3.2939 0 Td
(the)Tj
1.4683 0 Td
(major)Tj
2.6078 0 Td
(factors)Tj
2.9027 0 Td
(in)Tj
1.0375 0 Td
(these)Tj
2.2507 0 Td
(assays)Tj
2.6248 0 Td
(that)Tj
1.7802 0 Td
(might)Tj
-34.4917 -1.3039 Td
(influence)Tj
3.9174 0 Td
(the)Tj
1.4683 0 Td
(results)Tj
2.8063 0 Td
(and)Tj
1.7348 0 Td
(limit)Tj
2.1146 0 Td
(cross)Tj
2.2451 0 Td
(comparability)Tj
5.7656 0 Td
(between)Tj
3.5319 0 Td
(studies.)Tj
3.2088 0 Td
(The)Tj
1.7859 0 Td
(aim)Tj
1.7404 0 Td
(was)Tj
1.6951 0 Td
(also)Tj
1.7688 0 Td
(to)Tj
-33.783 -1.2983 Td
(develop)Tj
3.3165 0 Td
(solutions)Tj
3.8437 0 Td
(and)Tj
1.7348 0 Td
(reagents)Tj
3.5433 0 Td
(to)Tj
1.0261 0 Td
(overcome)Tj
4.1499 0 Td
(variability)Tj
4.2179 0 Td
(to)Tj
1.0262 0 Td
(enhance)Tj
3.5489 0 Td
(cross)Tj
2.2451 0 Td
(study)Tj
2.3924 0 Td
(comparative)Tj
-31.0448 -1.2983 Td
(data)Tj
1.9105 0 Td
(analysis)Tj
3.3278 0 Td
(and)Tj
1.7292 0 Td
(evaluation,)Tj
4.5864 0 Td
(without)Tj
3.3335 0 Td
(real)Tj
1.6951 0 Td
(head-to-head)Tj
5.5502 0 Td
(comparisons,)Tj
5.5616 0 Td
(thereby)Tj
3.2258 0 Td
(accelerating)Tj
4.9832 0 Td
(the)Tj
-35.9033 -1.3039 Td
(development)Tj
5.4084 0 Td
(of)Tj
1.0148 0 Td
(vaccines)Tj
3.5546 0 Td
(for)Tj
1.389 0 Td
(globally)Tj
3.3278 0 Td
(important)Tj
4.2803 0 Td
(pathogens)Tj
4.303 0 Td
(including)Tj
4.0422 0 Td
(TB,)Tj
1.6327 0 Td
(malaria)Tj
3.2258 0 Td
(and)Tj
1.7348 0 Td
(HIV.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 273.9968 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F12 1 Tf
0 -1.4976 Td
(Standard)Tj
4.0441 0 Td
(curve)Tj
2.4898 0 Td
(analysis)Tj
3.5055 0 Td
(as)Tj
1.0677 0 Td
(stage-gates)Tj
4.7717 0 Td
(for)Tj
1.4693 0 Td
(each)Tj
2.0882 0 Td
(analyte)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 239.0173 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Within)Tj
3.0954 0 Td
(the)Tj
1.4683 0 Td
(EC)Tj
1.4513 0 Td
(FP7)Tj
1.7802 0 Td
(EURIPRED)Tj
4.9776 0 Td
(consortium)Tj
4.8472 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(www.EURIPRED.)Tj
7.6025 0 Td
(eu)Tj
0 g
(\))Tj
1.508 0 Td
(18)Tj
1.1735 0 Td
(cytokines)Tj
3.9969 0 Td
(and)Tj
1.7291 0 Td
(chemo-)Tj
-33.63 -1.3039 Td
(kines)Tj
2.313 0 Td
(were)Tj
2.126 0 Td
(selected)Tj
3.3448 0 Td
(commercially)Tj
5.658 0 Td
(available)Tj
3.668 0 Td
(multiplex)Tj
4.0308 0 Td
(bead)Tj
2.109 0 Td
(assays)Tj
2.6248 0 Td
(were)Tj
2.126 0 Td
(ordered)Tj
3.3732 0 Td
(for)Tj
1.3833 0 Td
(these)Tj
2.2564 0 Td
(ana-)Tj
-35.0133 -1.2982 Td
(lytes.)Tj
2.228 0 Td
(Reagents/)Tj
4.1272 0 Td
(kits)Tj
1.6384 0 Td
(were)Tj
2.126 0 Td
(purchased)Tj
4.3313 0 Td
(from)Tj
2.2053 0 Td
(3)Tj
0.6973 0 Td
(different)Tj
3.6567 0 Td
(lots)Tj
1.6328 0 Td
(\(batches\))Tj
3.8721 0 Td
(from)Tj
2.2053 0 Td
(each)Tj
2.0296 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(4)Tj
0.6916 0 Td
(different)Tj
-33.9304 -1.2983 Td
(selected)Tj
3.3448 0 Td
(manufacturers)Tj
6.0491 0 Td
(\(Bio-Rad,)Tj
4.0762 0 Td
(Millipore,)Tj
4.1839 0 Td
(Ebiosciences,)Tj
5.5219 0 Td
(R&D)Tj
2.2847 0 Td
(systems\))Tj
3.6396 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8199 0 Td
(1A)Tj
0 g
(\).)Tj
1.9445 0 Td
(Each)Tj
2.177 0 Td
(man-)Tj
-35.0416 -1.3039 Td
(ufacturer)Tj
3.8834 0 Td
(provided)Tj
3.8154 0 Td
(three)Tj
2.2677 0 Td
(sets)Tj
1.6611 0 Td
(of)Tj
1.0148 0 Td
(kits)Tj
1.6441 0 Td
(from)Tj
2.2053 0 Td
(one)Tj
1.7008 0 Td
(lot,)Tj
1.4967 0 Td
(which)Tj
2.6475 0 Td
(were)Tj
2.126 0 Td
(then)Tj
2.0182 0 Td
(sent)Tj
1.8482 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
1.4683 0 Td
(3)Tj
0.6973 0 Td
(participating)Tj
-31.521 -1.2983 Td
(laboratories)Tj
4.9435 0 Td
(\(labs\))Tj
2.4492 0 Td
(for)Tj
1.3889 0 Td
(data)Tj
1.9106 0 Td
(comparison)Tj
4.9776 0 Td
(using)Tj
2.3924 0 Td
(the)Tj
1.4683 0 Td
(same)Tj
2.2564 0 Td
(lot)Tj
1.2699 0 Td
(when)Tj
2.4038 0 Td
(tested)Tj
2.5568 0 Td
(by)Tj
1.1792 0 Td
(each)Tj
2.0296 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(3)Tj
0.6974 0 Td
(labs)Tj
-34.4067 -1.2982 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1A)Tj
0 g
(\).)Tj
1.9445 0 Td
(In)Tj
1.1055 0 Td
(addition,)Tj
3.8268 0 Td
(2)Tj
0.6973 0 Td
(more)Tj
2.3414 0 Td
(lots)Tj
1.6271 0 Td
(from)Tj
2.211 0 Td
(each)Tj
2.0239 0 Td
(manufacturer)Tj
5.692 0 Td
(were)Tj
2.1203 0 Td
(tested.)Tj
2.7779 0 Td
(Each)Tj
2.177 0 Td
(lab)Tj
1.406 0 Td
(tested)Tj
2.5511 0 Td
(addi-)Tj
-34.3216 -1.2983 Td
(tional)Tj
2.5171 0 Td
(lots)Tj
1.6327 0 Td
(from)Tj
2.2111 0 Td
(a)Tj
0.6519 0 Td
(different)Tj
3.6567 0 Td
(manufacturer,)Tj
5.913 0 Td
(to)Tj
1.0262 0 Td
(minimize)Tj
4.0421 0 Td
(bias)Tj
1.7915 0 Td
(towards)Tj
3.4016 0 Td
(possibly)Tj
3.4412 0 Td
(confounding)Tj
5.3801 0 Td
(lab)Tj
-35.6652 -1.3039 Td
(specific)Tj
3.1917 0 Td
(parameters)Tj
4.6715 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1A)Tj
0 g
(\).)Tj
1.9446 0 Td
(In)Tj
1.1112 0 Td
(addition,)Tj
3.821 0 Td
(a)Tj
0.652 0 Td
(third)Tj
2.2167 0 Td
(party)Tj
2.296 0 Td
(universal)Tj
3.8495 0 Td
(detection)Tj
3.9401 0 Td
(reagent)Tj
3.1861 0 Td
(was)Tj
-32.7002 -1.2983 Td
(included)Tj
3.7133 0 Td
(as)Tj
1.0148 0 Td
(an)Tj
1.2019 0 Td
(extra)Tj
2.211 0 Td
(condition)Tj
4.1159 0 Td
(in)Tj
1.0318 0 Td
(all)Tj
1.1508 0 Td
(assays)Tj
2.6249 0 Td
(in)Tj
1.0318 0 Td
(all)Tj
1.1509 0 Td
(labs,)Tj
1.9899 0 Td
(in)Tj
1.0375 0 Td
(order)Tj
2.4207 0 Td
(to)Tj
1.0262 0 Td
(be)Tj
1.1508 0 Td
(able)Tj
1.8312 0 Td
(to)Tj
1.0205 0 Td
(compare)Tj
3.719 0 Td
(all)Tj
1.1452 0 Td
(kits,)Tj
-34.5881 -1.2983 Td
(using)Tj
2.3867 0 Td
(identical)Tj
3.6567 0 Td
(fluorescent)Tj
4.6374 0 Td
(detection)Tj
3.9402 0 Td
(reagents.)Tj
3.77 0 Td
(Finally,)Tj
3.1691 0 Td
(all)Tj
1.1452 0 Td
(labs)Tj
1.7688 0 Td
(tested)Tj
2.5512 0 Td
(exactly)Tj
2.9707 0 Td
(the)Tj
1.4683 0 Td
(same)Tj
2.2564 0 Td
(spiked)Tj
-33.7207 -1.3039 Td
(samples,)Tj
3.6056 0 Td
(reference)Tj
3.9175 0 Td
(standard)Tj
3.7247 0 Td
(and)Tj
1.7291 0 Td
(biological)Tj
4.0875 0 Td
(samples,)Tj
3.6113 0 Td
(with)Tj
1.9956 0 Td
(all)Tj
1.1452 0 Td
(kits)Tj
1.6441 0 Td
(and)Tj
1.7291 0 Td
(lots.)Tj
1.8595 0 Td
(In)Tj
1.1055 0 Td
(total)Tj
2.0069 0 Td
(20)Tj
1.1736 0 Td
(kits)Tj
1.6384 0 Td
(were)Tj
-34.9736 -1.2982 Td
(tested)Tj
2.5511 0 Td
(in)Tj
1.0375 0 Td
(this)Tj
1.6724 0 Td
(study)Tj
2.3868 0 Td
(allowing)Tj
3.6226 0 Td
(analysis)Tj
3.3222 0 Td
(of)Tj
1.0148 0 Td
(324)Tj
1.6498 0 Td
(standard)Tj
3.7247 0 Td
(curves.)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 360 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Multiplex)Tj
4.089 0 Td
(bead)Tj
2.4023 0 Td
(arrays)Tj
2.9481 0 Td
(benefit)Tj
3.1677 0 Td
(from)Tj
2.1969 0 Td
(commo)Tj
3.2315 0 Td
(n)Tj
0.7654 0 Td
(reference)Tj
4.3725 0 Td
(standard)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.02012)Tj
4.089 0 Td
(05)Tj
0 g
2.0906 0 Td
(September)Tj
5.0386 0 Td
(4,)Tj
1.0418 0 Td
(2018)Tj
32.8254 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
48 0 obj
<>stream
endstream
endobj
49 0 obj
<>stream
endstream
endobj
50 0 obj
<>stream
endstream
endobj
51 0 obj
<>stream
endstream
endobj
52 0 obj
<>stream
endstream
endobj
53 0 obj
<>stream
BT
66.402 0 Td
(17)Tj
ET
Q
endstream
endobj
54 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 57 0 R/Contents 58 0 R/TrimBox[0 0 612 792]>>
endobj
56 0 obj
<>stream
xwy~|}ʠ=N[mjzZ+zjU*2Ld
Cg3ȤCo˘7;Ix+kgk_+Y9 @ @ @ :/=ψ @ @ @ @ @ 7@Y?NƳo"N @ @ @ @ @hul#7o%@ @ @ @ @ p 䛨nk.7%@ @ @ @ @ @Fhuv7ok$@ @ @ @ @ p \g^.++`]/ @ @ 4O #tv] @ @ @ufiu @ @ @K
\wi]] @ @ t.<i);uEuoN0v.I @ @ @@lU9~[ @ @ @#ZN7x!#eeeMڭ @ @ @(d+7%@ @ @ vhI84hgR] @ @ @@"sln. @ @ @@ȳݼ+MXbyyE @ @ ./Z)-Dwy
H @ @ \u-9jmK @ @ URsW. @ @ tRm;cUՖ{ @ @ @K
4XLK( @ @ t"<-<{