State of The Science in Dried Blood Spot

Clinical Chemistry 64:4
656–679 (2018) Review
State of the Science in Dried Blood Spots

Jeffrey D. Freeman,1* Lori M. Rosman,2 Jeremy D. Ratcliff,3 Paul T. Strickland,4 David R. Graham,5 and
Ellen K. Silbergeld4
BACKGROUND: Advancements in the quality and avail- Technological advancements will likely continue to min-
ability of highly sensitive analytical instrumentation and imize constraints around DBS adoption.
methodologies have led to increased interest in the use of
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© 2017 American Association for Clinical Chemistry
microsamples. Among microsamples, dried blood spots
(DBS) are the most well-known. Although there have
been a variety of review papers published on DBS, there Recent advancements in the quality and availability of
has been no attempt at describing the full range of ana- highly sensitive analytical instrumentation have led to
lytes measurable in DBS, or any systematic approach increased interest in the use of microsamples (i.e., biolog-
published for characterizing the strengths and weaknesses ical samples of ⬍50 ␮L) (1–3 ). Microsamples have been
associated with adoption of DBS analyses. applied for basic and clinical research, public health, and
clinical medicine (4 –9 ). Interest in microsampling has
CONTENT: A scoping review of reviews methodology was been driven, in part, by the development of sophisticated
used for characterizing the state of the science in DBS. computer software programs and methodological plat-
We identified 2018 analytes measured in DBS and found forms for improved qualitative and quantitative analysis
every common analytic method applied to traditional (10 –13 ). Among microsampling methods, dried blood
liquid samples had been applied to DBS samples. Ana- spots (DBS)6 are the most well-known and researched.
lytes covered a broad range of biomarkers that included DBS are a minimally invasive method for the collection
genes, transcripts, proteins, and metabolites. Strengths of of small quantities of whole blood from finger or heel
DBS enable its application in most clinical and labora- stick with application to specially prepared filter paper for
tory settings, and the removal of phlebotomy and the drying (14, 15 ). DBS samples do not require phlebot-
need for refrigeration have expanded biosampling to omy, and DBS can be stored and shipped under ambient
hard-to-reach and vulnerable populations. Weaknesses conditions, although a comprehensive assessment of ana-
may limit adoption in the near term because DBS is a lyte stability has not been performed (16, 17 ). Existing
stability studies for DBS, although limited, have demon-
nontraditional sample often requiring conversion of
strated analyte stability across a wide range of storage
measurements to plasma or serum values. Opportunities
conditions (18 ).
presented by novel methodologies may obviate many of
To date, DBS have a range of applications in clinical
the current limitations, but threats around the ethical use
practice, basic research, and population-based research
of residual samples must be considered by potential (4, 5, 15, 19, 20 ). The most common and widely ac-
adopters. cepted clinical use of DBS is for newborn screening pro-
grams, which are primarily concerned with the detection
SUMMARY: DBS provide a wide range of potential appli- of metabolic disorders (21 ). Other clinical applications
cations that extend beyond the reach of traditional sam- in the published literature have focused on HIV surveil-
ples. Current limitations are serious but not intractable. lance, therapeutic drug monitoring, and clinical chemis-
try (8, 21–24 ). Basic research applications for DBS
include biomarker development and validation, drug dis-
covery and development, forensic science, systems biol-
ogy, and toxicology (5, 17, 25–27 ). Population-based
1
National Health Mission Area, Johns Hopkins University Applied Physics Laboratory, research applications are variable but may be broadly cat-
Laurel, MD; 2 Welch Medical Library, Johns Hopkins University, Baltimore, MD; 3 Public
Health Studies Program, Krieger School of Arts and Sciences, Johns Hopkins University,
egorized into human epidemiological studies and envi-
Baltimore, MD; 4 Department of Environmental Health and Engineering, Bloomberg ronmental population studies (5, 17, 28, 29 ).
School of Public Health, Johns Hopkins University, Baltimore, MD; 5 Department of Mo-
lecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University,
Baltimore, MD.
* Address correspondence to this author at: JHU/APL, 11100 Johns Hopkins Road, Rm.
21-S360, Laurel, MD 20723. Fax 410-955-0617; e-mail jeffrey.freeman@jhuapl.edu.
6
Received May 9, 2017; accepted September 25, 2017. Nonstandard abbreviations: DBS, dried blood spots; SRR, scoping review of reviews;
Previously published online at DOI: 10.1373/clinchem.2017.275966 SWOT, Strengths, Weaknesses, Opportunities, and Threats; VOC, volatile organic
© 2017 American Association for Clinical Chemistry compound.
656
Review
As interest in DBS analyses continues to increase, An information specialist from the Welch Medical
potential adopters will need to quickly, effectively, and Library at Johns Hopkins University developed and con-
systematically assess the utility of DBS for their respective ducted the literature search after input from the research
purposes. Understanding the strengths and weakness, as team. We searched PubMed, Embase, and CaPlus. We
well as potential opportunities and threats, is essential for used a combination of controlled vocabulary and key-
adopters to avoid false starts and ensure effective and words to search for review papers and validation studies
appropriate adoption of DBS sampling to a specific goal. involving DBS. References from included studies and
Furthermore, a comprehensive list of current and poten- review articles were hand-searched to identify any addi-
tial analytes, as well as their respective analytic methods, tional relevant studies for analysis. A summary of search
could help adopters assess the potential of DBS. Al- terms and strategies is presented in Table 1 of Appendix

though there have been a variety of review articles pub- A in the online Data Supplement. All citations were im-
lished on DBS methods, there has been no systematic ported into the EndNote citation management system,
assessment of the strengths and weaknesses of DBS, and and duplicates were removed. We used Covidence, a
attempts at compiling a comprehensive list of analytes Web-based systematic review software program, for title/
validated in DBS have been limited in scope. abstract and full text review. We followed a dual review
The objective of this review was to apply a systematic process with each reviewer blinded to the other reviewer’s
approach to characterizing the state of the science in decision. Conflicts were resolved by a third reviewer. A
DBS. We aimed to characterize the state of the science detailed description of all methods is provided in the
through identification of strengths, weaknesses, opportu- Methods section of Appendix A in the online Data
nities, and threats, and by compiling a comprehensive list Supplement.
of analytes and their respective analytic methods as iden-
tified in the published literature. Results
Of the 1636 citations identified for screening, 86 studies

Methods
were selected for inclusion in the review (see Fig. 1 in
Appendix A of the online Data Supplement). There were
Because the existing body of literature on DBS is vast and
71 review papers, 13 commentaries or short reports, and
diverse, a scoping review of reviews (SRR) methodology
2 technical reports included (see Table 2 in Appendix A
was used for identifying the relevant evidence and map-
of the online Data Supplement).
ping key concepts for DBS (30 –33 ). Our overall ap-
proach included the following 5 stages: (a) establishing
ANALYTE DATABASE
the research question, (b) identifying relevant studies, (c)
We identified 2018 unique analytes measured from DBS
study selection, (d) charting the data, and (e) collating, samples. A comprehensive list of analytes divided by class
summarizing, and reporting the results. is provided in Table 1. Of the 2018 unique analytes
Consistent with common uses of SRRs, our study measured, 50% (n ⫽ 1001) were classified as small mol-
aimed to summarize the state of the science for DBS, a ecule, 33% (n ⫽ 677) as large molecule, 15% (n ⫽ 309)
topic with a wide range of applications. Our review char- as nucleic acid, and 2% (n ⫽ 31) as element (Fig. 1). The
acterizes the state of the science around DBS for policy range of analytes identified in Table 1 includes genomic,
makers, researchers, and practitioners who may otherwise epigenomic, transcriptomic, proteomic, and metabolo-
lack the time, resources, or expertise to undertake such an mic markers. In the area of infectious diseases, Table 1
endeavor (34 ). To this end, we have adapted the Goert- includes analytes for viral, bacterial, parasitic, and proto-
zen et al. methods for use in our study (33 ). These meth- zoan detection (29, 37 ). Additionally, Table 1 includes a
ods have been modified to include (a) snowball methods wide range of analytes classified as markers of exposure, as
and SWOT (Strengths, Weaknesses, Opportunities, and well as health and disease status (5, 7, 21, 28, 29 ).
Threats) methods for use in data extraction and (b) a All common analytic methods currently applied to
form of quality assessment described in the Methods sec- traditional liquid samples were found to have been ap-
tion of Appendix A in the Data Supplement that accom- plied to DBS. To better characterize common DBS ap-
panies the online version of this article at http://www. plications in the literature, we examined the combination
clinchem.org/content/vol64/issue4 (35 ). We have in- of unique analytes with their respective analytic methods.
cluded these modifications to address weaknesses identi- We found 3289 unique analyte/analytic method combi-
fied in SRR methodologies by Levac et al. (35, 36 ). A nations. For classification, we assigned 1 of the following
rigorous and iterative approach to each stage, consistent categories to each analytic method identified in the liter-
with current SRR methods and the stated modifications, ature: mass spectrometry, immunoassay, nucleic acid-
is described in the Methods section of Appendix A found based method (e.g., PCR), separation (chromatography),
in the online Data Supplement. separation (electrophoresis), separation (other), spectros
Clinical Chemistry 64:4 (2018) 657

658
Review
Table 1. Comprehensive list of analytes identified in the literature to have been measured in DBS.
Clinical Chemistry 64:4 (2018)
Small molecule
(1-(2-Morpholin-4-ylethyl)indol-3-yl)-naphthalen-1- 11-Eicosenoic acid 2,2’,3,4’,5,5’,6-Heptachlorobiphenyl

ylmethanone 11-Hydroxytetrahydrocannabinol 2,2’,4,4’-Tetrabromodiphenyl ether
(4-Methyl-1-naphthyl)-(1-pentylindol-3- 11-nor-9-Carboxy-tetrahydrocannabinol 2,2’,4,4’,5-Pentabromodiphenyl ether
yl)methanone 11-nor-9-Carboxy-tetrahydrocannabinol 2,2’,4,4’,5,5’-Hexabromodiphenyl
1␤-Hydroxycholic acid glucuronide 2,2’,4,4’,5,5’-Hexabromodiphenyl ether
1-(3,4-Methylenedioxybenzyl)-piperazine 13,16-Docosadienoic acid 2,2’,4,4’,5,5’-Hexachlorobiphenyl
1-(5-fluoropentyl)-3-(1-naphthoyl)indole 17-␣-Hydroxypregnenolone 2,2’,4,4’,5,6’-Hexabromodiphenyl ether
1-(9Z,12Z-Octadecadienoyl)-sn-glycero-3- 17-␣-Hydroxyprogesterone 2,2’,4,4’,6-Pentabromodiphenyl ether
phosphocholine 2-(2,5-Dimethoxy-4-propylphenyl)ethanamine 2,3,3’,4,4’-Pentachlorobiphenyl
1-Arachidoyl-2-hydroxy-sn-glycero-3- 2-(4-Iodo-2,5-dimethoxyphenyl)ethan-1-amine 2,3,7,8-Tetrachlorodibenzo-p-dioxin
phosphocholine 2-[(1S,3R)-3-hydroxycyclohexyl]-5-(2-methyloctan-2- 2,3’,4,4’,5-Pentachlorobiphenyl
1-Behenoyl-2-hydroxy-sn-glycero-3-phosphocholine yl)phenol 2,4-Dihydroxybutanoic acid
1-Dodecanoyl-2-tridecanoyl-sn-glycero-3- 2-[2,5-Dimethoxy-4-(propylsulfanyl)phenyl]ethan-1- 2,4,4’-Tribromodiphenyl ether
phosphate amine 2,4,4’-Trichlorobiphenyl
1-Hexacosanoyl-2-hydroxy-sn-glycero-3- 2-[4-(Ethylsulfanyl)-2,5-dimethoxyphenyl]ethan-1- 2,4,6-Trimethoxyamphetamine
phosphocholine amine 2,5-Dimethoxy-4-bromophenethylamine
1-Hexyl-3-(naphthalen-1-oyl)indole 2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4- 2,5-Dimethoxy-4-ethylphenethylamine
1-Lignoceroyl-2-hydroxy-sn-glycero-3- (4-methylpiperazin-1-yl)phenyl)amino)-1H- 2,5-Dimethoxy-4-isopropylthiophenethylamine
phosphocholine pyrazolo[3,4-d] pyrimidin-3(2H)-one 2,5-Dimethoxy-4-methylamphetamine
1-Methylhistidine 2-Aminoisobutyric acid 2,5-Dimethoxy-4-methylphenethylamine
1-O-hexadecyl-2-hydroxy-sn-glycero-3- 2-Deoxytetronic acid 2,5-Dimethoxyphenethylamine
phosphocholine 2-Ethyl-5-methyl-3,3-diphenylpyrroline 2’-Deoxyguanosine
1-O-octadecyl-2-hydroxy-sn-glycero-3- 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine 2’-Deoxyinosine
phosphocholine 2-Furoic acid 2’R-ochratoxin A
1-Oleoyl-2-hydroxy-sn-glycero-3-phosphocholine 2-Hydroxyadipic acid 21-Deoxycortisol
1-Oleoyl-2-hydroxy-sn-glycero-3- 2-Hydroxybutyric acid 25-Hydroxyvitamin D2
phosphoethanolamine 2-Hydroxydocosanoic acid 26-Hydroxycholesterol-3-sulfate
1-Palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine 2-Hydroxyisocaproate 3-epi-25-Hydroxyvitamin D3
1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol 2-Hydroxyisovalerate 3-Fluoromethcathinone
1-Pentyl-3-(1-naphthoyl)indole 2-Hydroxysebacic acid 3-Hexenedioic acid
1-Pentyl-3-(2-methoxyphenylacetyl)indole 2-Methylbutyrylcarnitine 3-Hydroxyquinine
1-Stearoyl-2-hydroxy-sn-glycero-3-phosphocholine 2-Methylbutyrylglycine 3-Hydroxy-decanoylcarnitine
1,1-Dichloro-2,2-bis(4-chlorophenyl)ethene 2-Methylcitrate 3-Hydroxy-dodecanoylcarnitine
1,1,1-Trichloro-2-(2-chlorophenyl)-2-(4- 2-Oxo-3-hydroxy-lysergic acid diethylamide 3-Hydroxy-hexadecanoylcarnitine
chlorophenyl)ethane 2-Oxoadipic acid 3-Hydroxy-hexanoylcarnitine
1,2-Diheptadecanoyl-sn-glycero-3-phosphate 2-Propylglutaric acid 3-Hydroxy-iso-/butyrylcarnitine
1,2,3,7,8-Pentachlorodibenzo-p-dioxin 2,2’,3,3’,4,4’,5-Heptachlorobiphenyl 3-Hydroxy-isovalerylcarnitine
1,3-Benzodioxolyl-N-methylbutanamine 2,2’,3,3’,4,4’,5,5’-Octachlorobiphenyl 3-Hydroxy-octadecadienoylcarnitine
1’-Hydroxymidazolam 2,2’,3,3’,4,4’,5,5’,6-Nonachlorobiphenyl 3-Hydroxy-octadecanoylcarnitine
10-Hydroxydecenoic acid 2,2’,3,3’,4,4’,5,5’,6,6’-Decachlorobiphenyl 3-Hydroxy-octadecenoylcarnitine
11-Deoxycorticosterone 2,2’,3,4,4’,5,5’-Heptachlorobiphenyl 3-Hydroxy-octanoylcarnitine
11-Deoxycortisol 2,2’,3,4,4’,5’-Hexachlorobiphenyl 3-Hydroxy-stearoylcarnitine
Continued on page 659

Table 1. Comprehensive list of analytes identified in the literature to have been measured in DBS. (Continued from page 658)
Small molecule
3-Hydroxy-tetradecanoylcarnitine 4-Methylumbelliferyl ␤-D-galactopyranoside Aflatoxin G2

3-Hydroxydodecanedioic acid 4-Nitrophthalic acid Aflatoxin M1
3-Hydroxyglutaric acid 4’-Hydroxyflurbiprofen Alanine
3-Hydroxyhexadecanoic acid 5-Hydroxyhexanoic acid Aldrin
3-Hydroxyisovaleric acid 5-Hydroxyindoleacetic acid Alfentanil
3-Hydroxypalmitoylcarnitine 5-Hydroxymethyl-2-furoic acid Allantoin
3-Hydroxyproline 5-Hydroxypropafenone ␣-Cyano-4-hydroxycinnamic acid
3-Hydroxypropionate 5-Iodo-2-aminoindane ␣-Aminoadipate
3-Hydroxypropionic acid 5-Methoxy-N,N-dimethyltryptamine ␣-Aminoadipic acid
3-Methyl-2-oxovaleric acid 5-Methyltetrahydrofolic acid ␣-Aminobutyric acid
3-Methyladipic acid 5-Sulfosalicylic acid ␣-Carotene
3-Methylbutanoic acid 5,6-Methylenedioxy-2-aminoindane ␣-Galactosylceramide
3-Methylcrotonylglycine 6-Monoacetylmorphine ␣-Hexachlorocyclohexane
3-Methylglutaconic acid 6-Prenylnaringenin ␣-Hydroxyalprazolam
3-Methylglutaric acid 7-Aminoclonazepam ␣-Hydroxyglutaric acid
3-Methylglutarylcarnitine 7-Aminoflunitrazepam ␣-Isoleucine
7-Dehydrocholesterol ␣-Ketoglutaric acid
3-Methylhistidine
7-Demethylated centchroman ␣-Ketoisocaproic acid
3,12-Dihydroxy-cholenic acid
7-Ethoxycoumarin ␣-Ketoisovaleric acid
3,3’,4,4’-Tetrachlorobiphenyl 7-Fluoro-4-(N,N- ␣-Ketomethylvaleric acid
3,4-Dihydroxy-L-phenylalanine dimethylaminosulfonyl)benzofurazan ␣-Ketooctanoic acid
3,4-Methylenedioxy-N-ethylamphetamine 7-Hydroxyoctanoic acid ␣-Linolenic acid
3,4-Methylenedioxyamphetamine 7-Octenedoic acid ␣-Methyltryptamine
3,4-Methylenedioxymethamphetamine 8-Dehydrocholesterol Alprazolam
3,4-Methylenedioxypyrovalerone 8-epi-Prostaglandin F2␣ Altenuene
3’,4’-Methylenedioxy-␣-pyrrolidinopropiophenone 8-Prenylnaringenin Alternariol
3␤-Hydroxy-5-cholenoic acid Abacavir Alternariol monomethyl ether
4-Aminobenzoic acid Abacavir glucuronide Ambrisentan
4-Aminophenyl-1-phenethylpiperidine Acetic acid Aminorex

4-Androstene-3,6,17-trione Acetoacetic acid Amiodarone
4-Androstenedione Acetonitrile Amisulpride
4-Androsterone glucuronide Aceturic acid Amitriptyline
4-Chlorophenylbiguanide Acetylcarnitine Amlodipine
4-Hydroxy propranolol ␤-D-glucuronide Aconitic acid Amodiaquine
4-Hydroxybenzoic acid Acyl glucuronide mycophenolic acid Amphetamine
4-Hydroxyhippuric acid Adenosine Amprenavir
4-Hydroxyphenyllactic acid Adipic acid Anabasine
4-Hydroxyphenylpyruvic acid
Review
Afimoxifene Anastrazole
4-methoxynaphthalen-1-yl-(1-pentylindol-3- Aflatoxin B1 Anatabine
yl)methanone Aflatoxin B1-lysine adduct Andarine
4-Methylethcathinone Aflatoxin B2 Apixaban
4-Methylthioamphetamine Aflatoxin G1 Arabinose

660
Review
Small molecule
Arachidic acid Buprenorphine glucuronide Citalopram

Arachidonic acid Bupropion Citric acid
Arachidoylcarnitine Busulfan Citrinin
Arginine Butabarbital Citrulline
Argininosuccinic acid Butalbital Clarithromycin
Aripiprazole Butorphanol Clenbuterol
Artemether Butylone Clobazam
Ascomycin C20 lysophosphatidylcholine Clomifene
Ascorbic acid C22 lysophosphatidylcholine Clomipramine
Asenapine C24 lysophosphatidylcholine Clonazepam
Asparagine C26 lysophosphatidylcholine Clonidine
Aspartic acid Caffeine Clopidogrel
Atazanavir Calcifediol Clozapine
Atenolol Canrenone Cobalamin C
Atracurium Capecitabine Cocaethylene
Atropine Caprylic acid Cocaine
Azelaic acid Captopril Codeine
Azithromycin Carbamazepine Codeine-6-glucuronide
Barbital Carbamazepine-10,11 epoxide Colchicine
Beauvericin Carboxymefloquine Coproporphyrin
Benazepril Carnosine Corticosterone
Benazeprilate Cathine Cortisol
Benzethonium chloride Cathinone Cortisone
Benzoic acid Cefotaxime Cotinine
Benzoylecgonine Ceftriaxone Creatine
␤-Alanine Cerotic acid Creatinine
␤-Carotene Chenodeoxycholic acid Cryptoxanthin
␤-Hexachlorocyclohexane Chitotriosidase Cycloguanil
Bile acid Chlordiazepoxide Cyclophosphamide
Biopterin Chlorodehydromethyltestosterone Cyclosporin A
Bisdesethylchloroquine Chloroquine Cystathionine
Bisoprolol Chlorthalidone Cysteine
Bisphenol A Cholestanetetrol glucuronide Cystine
Bosentan Cholesterol D-allo-Isoleucine
Brevetoxin Cholesterol sulfate D-Galactonic acid
Brinzolamide Choline theophyllinate D-Galactose-1-phosphate
Bromazepam Cimetidine Daclatasvir
Bromhexine Ciprofloxacin Daidzein
Bromperidol Cis-2-decenoic acid Dapsone
Budesonide Cis-4-decenoic acid Darunavir
Buprenorphine Cis-5-tetradecenoic acid Dasatinib

Small molecule
Decadienoylcarnitine Dimethoxyamphetamine Ergocalciferol

Decanoate Dimethoxybromoamphetamine Ertapenem
Decanoylcarnitine Dimethylone Erucic acid
Decenoylcarnitine Dimethylphenylpiperazinium Erythronic acid
Dehydroepiandrosterone sulfate Dipropyltryptamine Erythrose 4-phosphate
Δ-9-Tetrahydrocannabinol Dithioerythritol Estazolam
Δ-Alanine Dithiothreitol Estradiol
␦-Aminolevulinic acid DL-3-Phenyllactic acid Ethambutol
␦-Hexachlorocyclohexane DL-Sulforaphane N-acetyl-L-cysteine Ethanolamine
Deoxyadenosine Docetaxel Ethcathinone
Deoxycholic acid Docosahexaenoic acid Ethyl acetate
Dermatan sulfate Docosanoic acid Ethyl glucuronide
Desalkylflurazepam Docosapentaenoic acid Ethyl sulfate
Desbutyl-lumefantrine Docosatetraenoic acid Ethylenediaminetetraacetic acid
Desethyl-amodiaquine Dodecanoylcarnitine Ethylmalonic acid
Desethylchloroquine Dodecenoylcarnitine Ethylone
Desethylhydroxychloroquine Dolutegravir Etilamfetamine
Desipramine Dolutegravir glucoronide Etiocholanolone glucuronide
Desmethyl bosentan Domoic acid Etoposide
Desmethylclomipramine Donepezil Etravirine
Desmethylflunitrazepam Dopamine Everolimus
Desoxypipradol Doxazosin Exadecanedioylcarnitine
Desvenlafaxine Ecgonine methyl ester Exemestane
Dexamethasone Efavirenz Exenatide
Dexanabinol Eicosadienoic acid Exendin-4
Dextroamphetamine Eicosapentaenoic acid Fatty acid ester
Dextromethorphan Eicosatrienoic acid Fenfluramine
Dextrorphan Emixustat Fentanyl
Dextrose Emtricitabine Fexinidazole

Diazepam Emtricitabine triphosphate Fexinidazole sulfone
Dichlorodiphenyldichloroethylene Enalapril Fexinidazole sulfoxide
Dichlorodiphenyltrichloroethane Endoxifen Fexofenadine
Diclofenac acyl glucuronide Enniatin A Fipronil
Digitoxin Enniatin A1 Fipronil desulfinyl
Dihydroartemisinin Enniatin B Fipronil sulfone
Dihydrocodeine Enniatin B1 Flephedrone
Dihydrotestosterone Enrofloxacin Fluconazole
Review
Dihydroxy-cholestanoic acid Enterolactone Flunitrazepam
Dihydroxy-oxocholestenoic acid Ephedrine Fluoxetine
Dihydroxyacetone phosphate Epinephrine Flurazepam
Diisopropyltryptamine Equol Flurbiprofen

662
Review
Small molecule
Fluvoxamine Glycolic acid Hydroxytyrosol

Folate Guanfacine Hydroxytyrosol acetate-sulfate
Formiminoglutamic acid Guanidineacetic acid Hydroxytyrosol-3-O-sulfate
Formoterol Guanidinoacetate Hydroxyzine dihydrochloride
Frataxin Guanosine Hymecromone
Free carnitine Haloperidol Ibuprofen
Free erythrocyte porphyrins Heparan sulfate Ifosfamide
Free triiodothyronine Heptacarboxylporphyrin Iloperidone
Fructose 6-phosphate Heptadecanoic acid Imatinib
Fumaric acid Heptanoylcarnitine Imipramine
Fumonisin B1 Hexacarboxylporphyrin Indinavir
Fusidic acid Hexachlorobenzene Indole-3-acetic acid
Gabapentin Hexachlorocyclohexane Infliximab
Galactitol Hexacosanoyl lysophosphatidylcholine Inosine
Galactose Hexadecanoylcarnitine Irbesartan
␥-Aminobutyric acid Hexadecenoylcarnitine Irinotecan
␥-Carboxyglutamate Hexanoic acid Iso-/butyrylcarnitine
␥-Hydroxybutyric acid Hexanoylcarnitine Isocitric acid
Ganciclovir Hexanoylglycine Isoleucine
Gemifloxacin Hexose Isoniazid
Genistein Hippuric acid Isovaleryl-/2-Methylbutyrylcarnitine
Gentamicin Histidine Isovalerylglycine
Gentisic acid Homocysteine Isoxanthohumol
Glucocerebroside Homoserine Isoxanthopterin
Gluconic acid Homovanillic acid Keratan sulfate
Glucose HT-2 toxin Ketamine
Glucose 6-phosphate HT-2 toxin-4-glucoronic acid L-allo-Isoleucine
Glucose tetrasaccharide Hydrazine monohydrate L-allo-Isoleucine
Glutaconic acid Hydrochlorothiazide L-Hydroxyproline
Glutamate Hydrocodone Labetalol
Glutamic acid Hydroxy bosentan Lactic acid
Glutamine Hydroxy desmethyl bosentan Lamivudine
Glutaric acid Hydroxy-cholestanoic acid Lamotrigine
Glutarylcarnitine Hydroxy-palmitoleylcarnitine Lansoprazole
Glutathione Hydroxybupropion Lapatinib
Glyceraldehyde 3-phosphate Hydroxychloroquine Leucine
Glyceric acid Hydroxyflurbiprofen Levamisole
Glycerol Hydroxyisovalerylcarnitine Levetiracetam
Glycine Hydroxyomeprazole Levosulpiride
Glycochenodeoxycholic acid Hydroxypropranolol glucuronide Lidocaine
Glycocholic acid Hydroxysuberic acid Lignoceric acid

Small molecule
Lindane Methylcitric acid N-Acetylhexosamine

Linezolid Methylecgonine N-Depropylpropafenone
Linoleic acid Methylene blue N-Desalkylflurazepam
Lomefloxacin hydrochloride Methylene violet N-Desmethyl tramadol
Long chain polyunsaturated fatty acids Methylenedioxypyrovalerone N-Desmethylflunitrazepam
Loperamide Methylephedrine N-Desmethyltamoxifen
Lopinavir Methylhexaneamine N-Glycan
Loratadine Methylisopropyltryptamine N-Methyl-4-isoleucine cyclosporin
Lorazepam Methylmalonic acid N-Propionylglycine
Lormetazepam Methylmalonyl-/succinylcarnitine N,N-diallyl-5-methoxy tryptamin
Losartan Methylone N,N-Dimethylphenylalanine
Losartan carboxylic acid Methylparaben N,N-Dimethyltryptamine
Lumefantrine Methylphenidate N,O-didesmethyl tramadol
Lurasidone Methylsuccinic acid N’-(4-Acetylaminophenyl)-N,N-dimethylacetamidine
Lutein Metoprolol N’-(4-Aminophenyl)-N,N-dimethylacetamidine
Lycopene Metronidazole Nalorphine
Lysergic acid diethylamide Mevalonic acid Naphthalen-1-yl-(1-butylindol-3-yl)methanone
Lysine Midazolam Naphyrone
Lyso-globotriaosylsphingosine Miltefosine Naproxen
Lysophosphatidylethanolamine Mirtazapine Nelfinavir
Maleic acid Mono-2-ethylhexyl phthalate Nelfinavir mesylate hydrate
Malic acid Mono-3-methyl-5-dimethylhexyl phthalate Neopterin
Malonylcarnitine Mono-3-methyl-7-methyloctyl phthalate Netilmicin
Mavoglurant Monoacetyldapsone Nevirapine
Medazepam Monobenzyl phthalate Nicotine
Mefloquine Monobutyl phthalate Nifedipine
Meperidine Monocyclohexyl phthalate Nikethamide
Mephedrone Monodesethylchloroquine Nilotinib
Mesocarb Monoethyl phthalate Nitisinone

meta-Chlorophenylpiperazine Monomethyl phthalate Nitrazepam
Metandienone Monooctyl phthalate Non-ayl-l-carnitine
Metformin Morphine Norbuprenorphine
Methadone Morphine-3-glucuronide Norbuprenorphine glucuronide
Methamphetamine Morphine-6-glucuronide Nordiazepam
Methanol Moxifloxacin Norfentanyl
Methcathinone Mycophenolic acid Norfluoxetine
Methedrone Mycophenolic acid glucuronide Norketamine
Review
Methionine Mycotoxin ochratoxin A Nornicotine
Methotrexate Myristic acid Nortriptyline
Methotrexate polyglutamates N-Acetylaspartic acid O-Desmethyl metoprolol
Methylcitrate N-Acetylgalactosamine O-Desmethyl tramadol

664
Review
Small molecule
Octadecadienoylcarnitine Perchlorate Pristanic acid

Octadecanoylcarnitine Perchloric acid Procaine
Octadecenoylcarnitine Perfluorohexane sulfonate Progesterone
Octanoate Perfluorononanoic acid Proguanil
Octanoylcarnitine Perfluorooctane sulfonamide Proline
Octenoylcarnitine Perfluorooctane sulfonate Propafenone
Olanzapine Perfluorooctanoic acid Propionic acid
Oleic acid Phencyclidine Propionylcarnitine
Omeprazole Phenobarbital Propionylglycine
Ormeloxifene Phenol Propranolol
Ornithine Phenol glucuronide mycophenolic acid Proprionylcarnitine
Orotic acid Phentermine Propylglutarylcarnitine
Oseltamivir Phenylacetate Propylparaben
Oseltamivir acid Phenylacetic acid Prostaglandin A1
Oseltamivir carboxylate Phenylalanine Prostaglandin E2
Oxalic acid Phenyllactate Prostaglandin F2␣
Oxazepam Phenylpropanolamine Pseudoephedrine
Oxazepam glucuronide Phenylpropionylglycine Psychosine
Oxcarbazepine Phenylpyruvic acid Pterin
Oxepin Phenytoin Pyrimethamine
Oxycodone Phosphatidylcholine Pyroglutamic acid
Oxyphencyclimine Phosphatidylethanol Pyrovalerone
Paclitaxel Phosphoethanolamine Pyruvic acid
Paliperidone Phosphoric acid Quetiapine
Palmitic acid Phosphoserine Quinidine
Pantothenic acid Phytanic acid Quinine
para-Fluorophenylpiperazine Pimelic acid R-trans-4-Hydroxy-praziquantel
para-Methoxy-N-methylamphetamine Pioglitazone Raltegravir
para-Methoxyamphetamine Pipamperone Ramipril
para-Methoxyphenylpiperazine Pipecolic acid Ramoplanin
Paracetamol Piperacillin/tazobactam Ranitidine
Paracetamol glucuronide Piperaquine Reboxetine
Paracetamol sulfate Pivalic acid Retinol
Paraxanthine Pivaloylcarnitine Ribavirin
Paroxetine Posaconazole Ribavirin-5’-diphosphate
Pazopanib Pramipexole Ribavirin-5’-monophosphate
Peginesatide Prasugrel Ribavirin-5’-triphosphate
Pentacarboxylporphyrin Prazepam Ribose 5-phosphate
Pentazocine Praziquantel Ribulose 5-phosphate
Pentobarbital Prazosin Rifampicin
Pentylone Pregabalin Rifampin

Small molecule
Rifapentine Suberylcarnitine Tetradecenoylcarnitine

Rifaximin Suberylglycine Tetrahydrocannabinol
Risperidone Succinic acid Tetrahydroxy-cholestenoic acid
Ritonavir Succinylacetone Tetrasaccharide
Ropiramate Succinyladenosine Theobromine
Rosiglitazone Sufentanil Theophylline
Rufinamide Sulconazole Threonic acid
Salbutamol Sulfadoxine Threonine
Salicylic acid Sulfamethoxazole Tiglylcarnitine
Salmeterol Sulfate Tiglylglycine
Saquinavir Sulforaphane Topiramate
Sarcosine Sulforaphane glutathione Topotecan
Saxitoxin Sulphadoxine Tramadol
Sebacic acid Sunitinib trans-3’-Hydroxycotinine
Sebacylcarnitine T-2 mycotoxin Triazolam
Secobarbital Tacrolimus Tribendimidine
Sedoheptulose Tadalafil Trichloroacetic acid
Sedoheptulose 7-phosphate Tafenoquine Trifluoromethylphenylpiperazine
Serine Tamoxifen Triglyceride
Serotonin Tasquinimod Trihydroxy-cholestenoic acid
Sertindole Taurine Triiodothyronine
Sertraline Taurochenodeoxycholic acid Trimethoxyamphetamine
Sildenafil Taurocholic acid Triprolidine
Simvastatin Telaprevir Tris(2-carboxyethyl)phosphine
Sirolimus Telmisartan Tryptophan
Sisomicin Temazepam Tyrosine
Sitagliptin Temsirolimus Unconjugated 4’-hydroxyflurbiprofen
Sitamaquine Tenofovir Unconjugated testosterone
Sodium sulfite Tenofovir diphosphate Uracil

Sodium valproate Tenofovir disoproxil Urea
Somatomedin C Terfenadine Uric acid
Sorafenib Teriflunomide Uridine
Sotalol Testosterone Urocanic acid
Sphingomyelin Testosterone glucuronide Uroporphyrin
Sphingosine-1-phosphate Testosterone undecanoate Ursodeoxycholic acid
Stanozolol Tetrabromobisphenol A Valeric acid
Stearic acid Tetracosactide Valganciclovir
Review
Stearidonic acid Tetracosahexaenoic acid Valine
Stearoylcarnitine Tetracosapentaenoic acid Valproate
Strychnine Tetradecadienoylcarnitine Valproic acid
Suberic acid Tetradecanoylcarnitine Valsartan

666
Review
Large molecule
Vancomycin Acid ␣-glucosidase Anti-B-lymphocyte antigen CD20 monocodal

Vanillic acid Acid sphingomyelinase Antibody drug
Vanillylmandelic acid Actin, cytoplasmic-1 Anti-MSP-119 antibody
Vecuronium Acylamino-acid-releasing enzyme Anti-MSP2 antibody
Vemurafenib Adenine phosphoribosyltransferase Anti-Mullerian hormone
Venlafaxine Adenosine deaminase Antinuclear antibodies
Verapamil Adenosylhomocysteinase Antithrombin-III
Very long fatty acid chain Adenylate kinase isoenzyme 1 Apolipoprotein A1
Vincristine Adenylosuccinate lyase Apolipoprotein A2
Vitamin A Adiponectin Apolipoprotein A4
Vitamin B12 Adrenomedullin Apolipoprotein B
Vitamin C Afamin Apolipoprotein B100
Vitamin D Alanine transaminase Apolipoprotein C1
Vomitoxin Aldolase C Apolipoprotein C2
Vomitoxin-3-glucoronic acid ␣1-Antichymotrypsin Apolipoprotein C3
Voriconazole ␣2-Antiplasmin Apolipoprotein D
Warfarin ␣-Actin Apolipoprotein E
Xanthine ␣1-Antitrypsin Apolipoprotein L1
Xanthohumol ␣1-Antichymotrypsin Aquaporin 1
Xylulose 5-phosphate ␣1-B glycoprotein Arginase 1
Zaleplon ␣1-Microglobulin/bikunin precursor Arylsulfatase A
Zatebradine ␣2-HS-glycoprotein Arylsulfatase B
Zearalanone ␣2-Macroglobulin Aspartate aminotransferase
Zearalenone ␣-Enolase B-cell activating factor
Zeaxanthin ␣-Fetoprotein Babesia microti antibody
Zidovudine ␣-Galactosidase Band 3 anion transport protein
Ziprasidone ␣-Glycosidase Bartonella quintana antibody
Zolpidem ␣-Hemoglobin-stabilizing protein ␤-Galactosidase
Zopiclone ␣-N-Acetylgalactosaminidase ␤-Globin
Zuclopenthixol ␣-Soluble NSF attachment protein ␤-2-Glycoprotein 1
␣-Synuclein ␤-Actin-like protein 2
Large molecule AMG 162 (therapeutic monoclonal antibody) ␤-Glucocerebrosidase
14–3-3 Protein ␤/␣ AMG 517 (therapeutic monoclonal antibody) ␤-glucosidase
14–3-3 Protein ␪ AMG A (therapeutic monoclonal antibody) ␤-Lipoprotein
14–3-3 Protein ␨/␦ AMG B (therapeutic monoclonal antibody) Betacellulin
26S Protease regulatory subunit 8 Amphiregulin Bifunctional purine biosynthesis protein PURH
3-Hydroxy-3-methylglutaryl-CoA lyase
3-Mercaptopyruvate sulfurtransferase Angiopoietin-1 receptor Biotinidase
6-Phospho-D-gluconate dehydrogenase, Angiotensin-converting enzyme Bisphosphoglycerate mutase
decarboxylating Angiotensinogen Blood group Rh(CE) polypeptide
␣-Thrombin Ankyrin Brain-derived neurotrophic factor
Acetylated hemoglobin Annexin A7 Brucella antibody

Large molecule
Butyrylcholinesterase Chylomicron Dengue virus antibody

C-C motif chemokine 19 Ciguatoxin Dermcidin
C-C motif chemokine 21 Cluster of differentiation 3 Dihydropteridine reductase
C-C motif chemokine 24 Cluster of differentiation 3␨ antibody Diphtheria antitoxin
C-peptide Cluster of differentiation 4 Diptheria antibody
C-reactive protein Clusterin Disialotransferrin
C-X-C motif chemokine 10 Coagulation factor XIIa heavy chain Drebrin-like protein
C-X-C motif chemokine 11 Coagulation factor XIII A chain E-selectin
C-X-C motif chemokine 13 Cofilin-1 Early activation antigen cluster of differentiation 69
C-X-C motif chemokine 5 Colistin Echinococcus antibody
C-X-C motif chemokine 9 Colony-stimulating factor 1 Echinococcus granulosus antibody
C1 inactin Complement component C1 inactivator Enolase 1
C3B inhibitor Complement component C1q subcomponent Entamoeba histolytica antibody
C4b-binding protein ␣ chain subunit C Enterotoxigenic Escherichia coli antibody
CA 242 Complement component C1s Epidermal growth factor
Calcitonin gene-related peptide Complement component C1s subcomponent Epidermal growth factor receptor
Calpain small subunit 1 Complement component C2 Epididymal secretory protein E4
Calpastatin Complement component C3 Epiregulin
Campylobacter antibody Complement component C3B inhibitor Epithelial cell adhesion molecule
Cancer antigen 125 Complement component C4 Epstein–Barr virus antibody
Carbonic anhydrase 1 Complement component C4 ␤ chain Erythrocyte acetylcholinesterase
Carbonic anhydrase 2 Complement component C4 ␥ chain Erythrocyte band 7 integral membrane protein
Carbonic anhydrase 3 Complement component C5 Erythrocyte membrane protein band 4.2
Carbonic anhydrase 9 Complement component C8 ␤ chain Erythropoietin
Carcinoembryonic antigen Complement component C9 Estrogen receptor
Carnitine-acylcarnitine translocase Complement factor 1 Etanercept
Carnosinase Complement factor B Eukaryotic translation initiation factor 5A-1
Caspase-3 COP9 signalosome complex subunit 3 Extracellular matrix metalloproteinase inducer
Catalase Coxiella burnetii antibody F-actin capping protein subunit ␤

Cathepsin D Creatine kinase F-box only protein 7
CD154 Creatine kinase B type Factor H
Ceruloplasmin Creatine kinase MM isoenzyme Factor V Leiden
Chemokine (C-C motif) ligand 2 Cryptosporidium antibody Fas antigen ligand
Chemokine (C-C motif) ligand 3 Cyclic AMP-responsive element-binding protein Fasciola hepatica antibody
Chemokine (C-C motif) ligand 4 3-like protein 4 Fatty acid binding protein 4
Chemokine (C-C motif) ligand 5 Cystatin B Fc-fusion protein
Chemokine (C-C motif) ligand 8 Cystatin C Ferritin
Review
Chemokine (C-X-C motif) ligand 2 Cytomegalovirus antibody Fetal hemoglobin
Chikungunya virus antibody D-Dopachrome decarboxylase Fibrinogen
Chlamydia trachomatis antibody Dactinomycin Fibrinogen ␣ chain
Chloride intracellular channel protein 1 ␦-Aminolevulinic acid dehydratase Fibrinogen ␤ chain
Cholinesterase Dematin Fibrinogen ␥ chain

668
Review
Large molecule
Fibrinopeptide A Growth hormone Herpes simplex virus 2 antibody

Fibroblast growth factor 2 Growth/differentiation factor 15 Herpes simplex virus antibody
Fibronectin Haptoglobin High-density lipoprotein
Filamin A, ␣ Heat shock 70 kDa protein 1 Histidine-rich glycoprotein
Filarioidea antibody Heat shock 70 kDa protein 2 Histone H2A type 1-H
Flavin reductase Heat shock 70 kDa protein 8 HIV antibody
Fms-related tyrosine kinase 3 ligand Heat shock protein 27 HIV p24 antigen
Folate receptor 1 Heat shock protein 90 HIV-1 antibody
Follicle-stimulating hormone Helicobacter pylori antibody HIV-1 envelope peptide
Follistatin Heme-binding protein 1 HIV-1 full-length core recombinant protein
Free-␤ human chorionic gonadotropin Hemoglobin HIV-1 polymerase
Fructose-bisphosphate aldolase A Hemoglobin A HIV-2 antibody
FT03 (peptide) Hemoglobin A1 Human chorionic gonadotropin
FT04 (peptide) Hemoglobin A2 Human papillomavirus antibody
FT05 (peptide) Hemoglobin C Human T-cell lymphotropic virus type 1 antibody
Fumarylacetoacetase Hemoglobin D Human T-cell lymphotropic virus type 2 antibody
Galactocerebroside ␤-galactosidase Hemoglobin D-Punjab Hydroxyacylglutathione hydrolase
Galactose-1-phosphate uridyltransferase Hemoglobin E Hypoxanthine-guanine phosphoribosyltransferase
Galactosylceramidase Hemoglobin Lepore Iduronate 2-sulfatase
Galectin-3 Hemoglobin O Arab Iduronidase
Gelsolin Hemoglobin S Immunoglobulin 64
Giardia antibody Hemoglobin subunit ␣ Immunoglobulin A
Giardia duodenalis antibody Hemoglobin subunit ␦ Immunoglobulin ␣-1 chain C region
Giardia lamblia antibody Hemoglobin subunit ␥1 Immunoglobulin E
Glial fibrillary acidic protein Hemoglobin subunit ␨ Immunoglobulin G
Glucose-6-phosphate dehydrogenase Hemopexin Immunoglobulin ␥1 chain C region
Glutamate-cysteine ligase regulatory subunit Hemozoin Immunoglobulin ␥2 chain C region
Glutaredoxin-1 Heparin cofactor 2 Immunoglobulin ␥3 chain C region
Glutaryl-CoA dehydrogenase Heparin-binding EGF-like growth factor Immunoglobulin ␥4 chain C region
Glutathione peroxidase 1 Hepatitis A virus antibody Immunoglobulin heavy chain V-1 region EU
Glutathione S-transferase A1 Hepatitis B virus core antibody Immunoglobulin heavy chain V-III region CAM
Glutathione S-transferase ␻1 Hepatitis B virus core antigen maternal antibody Immunoglobulin heavy chain V-III region GA
Glutathione S-transferase P Hepatitis B virus envelope antibody Immunoglobulin heavy chain V-III region GAL
Glycated hemoglobin Hepatitis B virus envelope antigen Immunoglobulin heavy chain V-III region TEI
Glyceraldehyde 3-phosphate dehydrogenase Hepatitis B virus surface antibody Immunoglobulin heavy chain V-III region TIL
Glycophorin A Hepatitis B virus surface antigen Immunoglobulin heavy chain V-III region TRO
Glycophorin C Hepatitis C virus antibody Immunoglobulin heavy chain V-III region WEA
Granulocyte macrophage colony-stimulating factor Hepatitis C virus antigen Immunoglobulin J chain
Granulocyte-colony stimulating factor Hepatitis C virus core antigen Immunoglobulin ␬ chain C region
Granulocyte–macrophage colony-stimulating factor Hepatocyte growth factor Immunoglobulin ␬ chain V-I region CAR
Green fluorescent protein Hepatocyte growth factor receptor Immunoglobulin ␬ chain V-I region DEE

Large molecule
Immunoglobulin ␬ chain V-I region Lay Interleukin 1␣ Latency-associated peptide transforming growth
Immunoglobulin ␬ chain V-I region Mev-like Interleukin 1␤ factor ␤1
Immunoglobulin ␬ chain V-I region Ni Interleukin 1 receptor antagonist protein Leishmania antibody
Immunoglobulin ␬ chain V-II region MIL Interleukin 10 Leishmania donovani promastigote antigen
Immunoglobulin ␬ chain V-II region RPMI 6410 Interleukin 11 Leptin
Immunoglobulin ␬ chain V-III region B6 Interleukin 12 Leptospira antibody
Immunoglobulin ␬ chain V-III region HAH Interleukin 13 Lipoprotein(a)
Immunoglobulin ␬ chain V-III region LOI Interleukin 17 receptor B Liver carboxylesterase 1
Immunoglobulin ␬ chain V-III region SIE Interleukin 17A Low molecular weight phosphotyrosine protein
Immunoglobulin ␬ chain V-III region VG (fragment) Interleukin 18 phosphatase
Immunoglobulin ␬ chain V-III region VH (fragment) Interleukin 2 Low-density lipoprotein
Immunoglobulin ␬ chain V-IV region (fragment) Interleukin 2 receptor subunit ␣ Lumican
Immunoglobulin ␬ chain V-IV region Len Interleukin 3 Luteinizing hormone
Immunoglobulin ␭ chain V-I region HA Interleukin 4 Lymphatic filariasis antibody
Immunoglobulin ␭ chain V-I region WAH Interleukin 5 Lymphocyte
Immunoglobulin ␭ chain V-III region LOI Interleukin 6 Lysosomal acid lipase
Immunoglobulin ␭ chain V-III region SH Interleukin 6 receptor Lysosomal b-d-galactosidase
Immunoglobulin ␭ chain V-IV region Hil Interleukin 6 receptor subunit ␣ Lysosomal-associated membrane protein 1
Immunoglobulin ␭ chain V-IV region MOL Interleukin 7 Lysozyme C
Immunoglobulin ␭1 chain C region Interleukin 8 M protein
Immunoglobulin ␭2 chain C region Interleukin 9 Macrophage colony-stimulating factor 1
Immunoglobulin ␭7 chain C region Islet autoantibodies Macrophage inflammatory protein-1␣
Immunoglobulin ␭ chain V region 4A Isovaleryl-CoA dehydrogenase Macrophage inflammatory protein-1␤
Immunoglobulin M Japanese encephalitis virus antibody Macrophage inflammatory protein-1␦
Immunoglobulin μ chain C region John Cunningham polyomavirus antibody Macrophage migration inhibitory factor
Immunoglobulin μ heavy chain disease protein KAI-9803 Macrophage-derived chemokine
Immunoglobulin ␥3 chain C region Kallikrein-11 Matrix metallopeptidase-9
Immunoreactive trypsin Kallikrein-6 Matrix metalloproteinase-3
Immunoreactive trypsinogen Keratin, type I cytoskeletal 10 Measles antibody

Importin subunit ␤1 Keratin, type I cytoskeletal 13 Medium-chain acyl-CoA dehydrogenase
Influenza A pdm09 virus antibody Keratin, type I cytoskeletal 14 Melanoma-derived growth regulatory protein
Insulin Keratin, type I cytoskeletal 9 Methylcrotonyl-CoA carboxylase
Insulin-like growth factor 1 Keratin, type II cytoskeletal 1 MHC class I polypeptide-related sequence A
Insulin-like growth factor binding protein 1 Keratin, type II cytoskeletal 2 epidermal Midkine
Insulin-like growth factor binding protein 2 Keratin, type II cytoskeletal 2 oral Mucin-like protein 1
Insulin-like growth factor binding protein 3 Keratin, type II cytoskeletal 5 Mumps virus antibody
Inter-␣-trypsin inhibitor heavy chain H1 Keratin, type II cytoskeletal 6A Mycobacterium leprae antibody
Review
Inter-␣-trypsin inhibitor heavy chain H2 Kininogen-1 Mycobacterium leprae phenolic glycolipid I
Inter-␣-trypsin inhibitor heavy chain H3 L-lactate dehydrogenase A chain antibody
Inter-␣-trypsin inhibitor heavy chain H4 L-lactate dehydrogenase B chain Myeloid differentiation primary response protein
Interferon-␥ L-selectin MyD88
Interleukin 1 Lactoferrin Myeloperoxidase

670
Review
Large molecule
Myosin-9 Platelet-derived growth factor B homodimer Retinal dehydrogenase 1

Myotrophin Platelet-derived growth factor subunit B Retinol-binding protein
N-Acetylgalactosamine-4-sulfatase Pregnancy-associated plasma protein A Ribonuclease inhibitor
N-Acetylgalactosamine-6-sulfatase Procalcitonin Rickettsia conorii antibody
N-Acetylmuramoyl-L-alanine amidase Programmed cell death protein 5 Rickettsia typhi antibody
Neurotrophin-3 Prolactin Rift Valley fever virus antibody
Neurotrophin-4 Prolidase Rubella virus antibody
Neutrophil activating peptide 2 Properdin S-Adenosyl-L-methionine:protein-L-isoaspartate O-
Nicotinate phosphoribosyltransferase Propionyl-CoA carboxylase methyltransferase
Norovirus antibody Prostasin S-Formylglutathione hydrolase
NSFL1 cofactor p47 Prostate-specific antigen S100 calcium-binding protein A4
Nucleoside diphosphate kinase A Proteasome activator complex subunit 2 S100 calcium-binding protein A6
Nucleoside diphosphate kinase B Proteasome inhibitor PI31 subunit S100 calcium-binding protein A8
Obg-like ATPase 1 Proteasome subunit ␣ type 2 S100 calcium-binding protein A9
Onchocerca volvulus antibody Proteasome subunit ␣ type 3 Salmonella LPS Group B antibody
Orientia tsutsugamushi antibody Proteasome subunit ␤ type 1 Salmonella LPS Group D antibody
Orosomucoid Proteasome subunit ␤ type 4 Saponin C
Osteoprotegerin Proteasome subunit ␤ type 6 Saposin C
Pancreatitis-associated protein Protein 4.1 Schistosoma antibody
Pappalysin-1 Protein C Selenium-binding protein 1
PEGylated-adnectin Protein deglycase DJ-1 Semenogelin-1
Pentasialotransferrin Protein disulfide-isomerase A2 Semenogelin-2
Peptidyl-prolyl cis-trans isomerase FKBP1A Protein S Serine/threonine-protein kinase OSR1
Peptidyl-prolyl isomerase A Protein S100-A9 Serine/threonine-protein phosphatase 2A 65 kDa
Peroxiredoxin-1 Protein tyrosine phosphatase, receptor type regulatory subunit A ␣ isoform
Peroxiredoxin-2 Protein-glutamine ␥-glutamyltransferase Serotransferrin
Peroxiredoxin-6 Proteins induced by Vitamin K absence Serpin B3
Phosphatidylethanolamine-binding protein Prothrombin Serum albumin
Phosphoglycerate kinase 1 Pseudomonas aeruginosa antibody Serum amyloid A
Placental growth factor Purine nucleoside phosphorylase Serum amyloid A-4 protein
Plasma cholinesterase Putative protein FAM10A4 Serum amyloid P
Plasma kallikrein Pyruvate kinase isozymes R/L Serum amyloid P component
Plasma protease C1 inhibitor Rab GDP dissociation inhibitor ␤ Serum paraoxonase/arylesterase 1
Plasma retinol-binding protein Ras-related nuclear protein Sex hormone binding globulin
Plasminogen Ras-related protein Rab-14 SH3 domain-binding glutamic acid-rich-like protein 3
Plasmodium falciparum antibody Ras-related protein Rab-1A Soluble transferrin receptor
Plasmodium falciparum multidrug resistance protein Receptor tyrosine-protein kinase erbB-2 Solute carrier family 2, facilitated glucose transporter
Plasmodium vivax antibody Receptor tyrosine-protein kinase erbB-3 member 1
Platelet basic protein Receptor tyrosine-protein kinase erbB-4 Somatotropin
Platelet endothelial cell adhesion molecule Regenerating islet-derived protein 4 Sorcin
Platelet-derived growth factor Respiratory syncytial virus antibody Spectrin ␣ chain, erythrocyte

Large molecule
Spectrin ␤, erythrocytic Transforming growth factor ␣ Uroporphyrinogen I synthetase

Stathmin Transforming growth factor ␤ Uroporphyrinogen III decarboxylase
Stem cell factor Transforming growth factor ␤1 UV excision repair protein RAD23 homolog A
Steroid 21-hydroxylase Transgelin-2 Vascular endothelial growth factor
Stress induced phosphoprotein 1 Transitional endoplasmic reticulum ATPase Vascular endothelial growth factor A
Strongyloides stercoralis antibody Transthyretin Vascular endothelial growth factor receptor 2
Substance P Treponema pallidum antibody Vascular endothelial growth factor D
Succinylaminoimidazole carboxamide riboside Treponema pallidum antigen Vasoactive intestinal peptide
Sulfamidase Treponema pertenue antigen Vibrio cholerae antibody
Superoxide dismutase Trichomonas vaginalis antibody Vitamin D-binding protein
Systemic lupus erythematosus antibody Triggering receptor expressed on myeloid cells 1 Vitronectin
T-complex protein 1 subunit ␤ Triose-phosphate isomerase von Willebrand factor
T-complex protein subunit epsilon Trisialotransferrin Zinc ␣2-glycoprotein
T-complex protein subunit zeta Tropomyosin ␣1 chain Zinc finger protein 410
Taenia solium antibody Tropomyosin ␣3 chain Zinc finger protein 611
Talin-1 Trypanosoma brucei antibody Zymogen granule protein 16 homolog B
Tartrate-resistant acid phosphatase Trypanosoma brucei antigen
Tetanus antibody Trypanosoma cruzii antibody Nucleic acid
Tetanus antitoxin Trypsin DNA
Tetrasialotransferrin Trypsin 1 DNA methylation
Thioredoxin Trypsinogen RNA
Threonine antibody Tubulin-specific chaperone A
Thrombin antibody Tumor necrosis factor ␣ Element
Thrombopoietin Tumor necrosis factor ␤ Aluminum
Thymosin ␤4-like protein 3 Tumor necrosis factor ligand superfamily member 14 Antimony
Thyroglobulin Tumor necrosis factor ligand superfamily member 8 Arsenic
Thyroid antibody Tumor necrosis factor receptor 1 Barium
Thyroid peroxidase antibody Tumor necrosis factor receptor 2 Beryllium
Bismuth
Thyroid-stimulating hormone Tumor necrosis factor receptor superfamily member 4 Cadmium
Thyrotropin Tumor necrosis factor receptor superfamily member 6 Calcium
Thyroxine Ubiquitin carboxyl-terminal hydrolase 14 Cesium
Thyroxine-binding globulin Ubiquitin carboxyl-terminal hydrolase 5 Chromium
Tissue factor Ubiquitin carboxyl-terminal hydrolase isozyme L3 Cobalt
Tissue plasminogen activator Ubiquitin thioesterase OTU1 Copper
Toxoplasma gondii antibody Ubiquitin-C Iodine
Transaldolase Ubiquitin-conjugating enzyme E2 variant 1 Iron
Transcortin UDP-glucose 4-epimerase Lead
Lithium
Review
Transcription elongation factor SPT6 UMP-CMP kinase Magnesium
Transferrin Uncharacterized protein C6orf163 Manganese
Transferrin receptor Uncharacterized protein C9orf40 Mercury
Transferrin-terbium glycoform Urokinase plasminogen activator surface receptor Molybdenum

Review
cally relevant to DBS are provided in Table 2. Our

Table 1. Comprehensive list of analytes identified in the SWOT analysis applied to the most common type of
literature to have been measured in DBS. (Continued from DBS sampling (i.e., sampling by finger or heel stick fol-
page 671) lowed by direct application to filter paper cards with
ambient storage). Although it was possible to use blood
Element
collected by venipuncture for volumetric application of
Nickel blood to filter paper cards, as well as cold storage to im-
Phosphorus prove analyte stability, these modifications removed sev-
Potassium
Rubidium eral of the key advantages of DBS methods, namely, sam-
Selenium pling without a phlebotomist or the need to keep samples

Sodium cool from the point of collection through to analysis (i.e.,
Sulfur
Thallium
cold chain).
Titanium
Vanadium STRENGTHS
Zinc DBS sampling is minimally invasive, requires only a
small volume of blood (i.e., ⬍50 ␮L), and uses simple
copy, and other. Of the 3289 combinations, 62% (n ⫽ collection methods (i.e., no centrifugation for plasma
2055) were classified as having been measured by mass preparation before storage) (4, 14, 38 ). DBS sampling
spectrometry, 17% (n ⫽ 553) by immunoassay, 11% typically involves prick of a finger or heel with a small
(n ⫽ 371) by nucleic acid-based method, 6% (n ⫽ 202) lancet followed by application of several drops of blood to
by separation (chromatography), 1% (n ⫽ 18) by sepa- filter paper cards for drying and storage. One of the key
ration (electrophoresis), ⬍1% (n ⫽ 12) by separation advantages to DBS sampling is the ability to derive a
(other), 2% (n ⫽ 54) by spectroscopy, and 1% (n ⫽ 24) volumetric amount of blood from a nonvolumetric ap-
by other (see the Analyte Database in Appendix B of the plication to filter paper (39 ). This is achieved by punch-
online Data Supplement). A complete list of all analytes ing a fixed diameter cylinder for analysis from a portion
with their corresponding analytic methods, classifica- of the dried spot that is assumed to be fully saturated on
tions, and original research references can be found in the the filter paper. This ability to derive a volumetric
Analyte Database in Appendix B of the online Data amount of blood, combined with minimally invasive
Supplement. methods, small sample volume, and simple collection,
allows DBS to be collected in the absence of a trained
SWOT ANALYSIS phlebotomist and may enable self-sampling or sampling
For the purposes of this investigation, only those outside of the traditional clinic or laboratory setting
strengths, weaknesses, opportunities, and threats specifi- (3, 8, 40 ). In terms of human sampling, these strengths
Fig. 1. Percentage of analyte classes assigned to unique analytes identified in the literature.
672 Clinical Chemistry 64:4 (2018)

Review
Table 2. SWOT analysis of common strengths, weaknesses, opportunities, and threats identified in the literature for DBS.
Strengths Weaknesses
Minimally invasive Nontraditional sample matrix
Small sample volume Small sample volume
Volumetric measurement Sampling from cold or dehydrated persons
Simple collection, transport, and storage Required drying
Reduced biohazard risk Pathogenicity of agents

Low cost Time, space, and labor-intensive processing
Reduced material input and waste Susceptibility to environmental conditions
Compatible with most bioanalytical methods Hematocrit effects
Versatile matrix Chromatographic effects
Wide range of analytes validated Sample heterogeneity
Good precision and reproducibility Differential analyte stability
Improved analyte stability Differential analyte extraction efficiency
Federal quality assurance program Poorly defined regulatory landscape
Federally established guidelines Additional validation steps
Published recommendations for validation methods Variability in validation methods applied
Opportunities Threats
Compliance with the 3Rs Use of residual samples
Centralization of labs Pediatric involvement in studies
Increased outpatient and offsite services Existing assays and work flows
Advancements in bioanalytical instruments Availability of experienced labs
Cost and availability of sophisticated instrumentation Regulatory uncertainty
Microfluidics and nanotechnology
Online/direct analyses
Endogenous indicators of blood hematocrit
Use of molar ratios
Sampling in hard-to-reach and vulnerable populations
Large, complex study design needs
In-field forensics
Sports drug testing
Personalized clinical reference ranges
Other dried matrices
3Rs, reduction, refinement, and replacement.
make DBS a preferred method for collecting blood from The dried matrix of DBS samples inactivates most
difficult-to-sample populations, such as neonates, elderly pathogens and thereby reduces biohazard risks associated
people, persons with damaged veins, or persons in remote with sample transport (6, 25, 45, 46 ). Reductions in
or underresourced environments (6, 8, 28 ). In terms of biohazard risks, combined with simple methods in stor-
sampling from animals, DBS can allow for reduction and age and transport (i.e., ambient conditions, no dry ice
refinement in the use of small or juvenile animals required), have allowed DBS to be considered exempt
(4, 41, 42 ). For example, by reducing the quantity of nonregulated materials; therefore, they are not subject to
blood collected and the invasiveness of the method, DBS hazardous material regulations in shipping (38 ). Materi-
use in toxicological studies can allow for serial sampling als required for DBS sampling are relatively low cost and
from the same animal, which reduces the total number of have few material inputs and waste (15, 47, 48 ). When
animals required, and allows researchers to no longer rely taken together, the reduction in material inputs, low cost,
on composite profiles, which improves overall data qual- ambient storage and transport, simple collection, and
ity (9, 43, 44 ). minimally invasive methods make DBS a suitable matrix

Review
Table 3. Comparison of DBS with traditional liquid plasma and serum.
Characteristics DBS Traditional plasma/serum
Matrix source Capillary blood (contains interstitial Venous blood

and intracellular fluids)
Matrix type Whole blood Plasma or serum
Matrix state Dried Liquid or frozen
Volume <50–100 μL >0.1–1.0 mL

Collection Ambient delayed storage (i.e., open-air Cold immediate storage (i.e., cold
drying followed by ambient storage) storage immediately after preparation)
Bioanalytical work flow Converted/modified Original/optimized
Measurement Converted/adjusted Direct
for biosampling in large or complex population-based manufacturers and end-users of DBS cards and helps
studies (5, 17 ). to improve the analytical sensitivity and reproducibil-
DBS samples are compatible with most bioanalytical ity of filter paper analyses (16 ). In addition to the
methodologies, which allows existing laboratories to eas- Newborn Screening Quality Assurance Program, DBS
ily adopt the technology (10 ). Aside from a hole-punch have easy-to-understand federally established guide-
device to remove a portion of sample for processing, all lines for collection and shipment (38 ). Although no
other material requirements for analyzing DBS samples federal or international bioanalytical validation meth-
should be readily available in most laboratories (16 ). ods have yet been fully established, DBS validation
DBS are also a versatile sample matrix. For example, any- methods were recommended in 2011 by the European
thing that can be measured from liquid whole blood, Bioanalysis Forum (44, 46, 55, 56 ).
plasma, or serum can, in principle, be measured in DBS
(29 ). Analytes representing a wide range of physico- WEAKNESSES
chemical properties have already been validated. To date, It is important for potential adopters to understand that
DBS samples have been used for a variety of viral, bacte- DBS is not a traditional plasma or serum sample (Table
rial, protozoan, and helminthic agents (29 ). DBS have 3). Differences between sample types may limit compa-
also been used to measure DNA, RNA, antibodies, pro- rability of measurements from DBS and constrain their
teins, drugs, metabolites, and an assortment of environ- application. There are notable differences between DBS
mental contaminants, among other analytes (Table 1). and plasma or serum. DBS samples come from capillary
DBS as a collection method has been demonstrated blood vs venous blood, consist of whole blood vs centri-
to achieve similar levels of precision and reproducibility fuged plasma or serum, are dried vs liquid or frozen, are
to that of traditional larger volume venous blood col- typically ⬍50 ␮L vs several milliliters, require open-air
lection in Vacutainer tubes or capillary pipettes drying before ambient storage vs immediate cold stor-
(16, 49 ). Compared with liquid samples, several ana- age, are analyzed with modified protocols vs those that
lyte classes in DBS have shown improved stability, were originally designed for plasma or serum, and of-
including analytes susceptible to degradation because ten have converted or adjusted measurements com-
of hydrolysis, photolytic processes, esterase, and RNAase pared with direct measurements for traditional sam-
action (28, 37, 43, 50, 51 ). Consequently, stability in DBS ples (16, 17, 29, 37, 44 ). Each of these differences
compared with liquid samples is particularly pronounced presents the opportunity to introduce bias into con-
for traditionally unstable analytes, such as RNA, cytokines, verted measurements taken from DBS samples, and
and several classes of drug metabolites (19, 48, 52, 53 ). Im- although DBS have often been successfully adjusted to
proved stability for some analytes, such as RNA and other corresponding plasma and serum values, the underly-
analytes susceptible to degradation because of hydrolysis, ing assumptions for adjustment must be validated be-
makes DBS not only more suited than traditional samples to fore DBS can be reliably used (53, 55 ).
some environments but also more suited to entire classes of The small volume of blood in DBS requires highly
analytes (43, 54 ). sensitive analytical instrumentation for accurate quanti-
The CDC has established an independent quality fication, and may limit DBS utility for repeat testing
control program, the Newborn Screening Quality As- (53, 55 ). The collection of DBS, although simple meth-
surance Program (38 ). The Newborn Screening Qual- odologically, may also be constrained by cold or dehy-
ity Assurance Program provides strict guidance to drated patients, in which case the amount or viscosity of

Review
the blood can be problematic for application and lead to ratio for target analytes, which can alter their measure-
uneven saturation of the filter paper and, ultimately, in- ments and bias attempts at conversion from DBS to
accurate estimation of starting volume from a fixed di- plasma (55, 65 ). Second, hematocrit directly affects the
ameter punch (5, 28 ). As previously mentioned, DBS viscosity of blood, which affects how a spot spreads and
samples require open-air drying for a minimum of 2 or saturates filter paper, which in turn limits volumetric
3 h before storage (57 ). This is problematic for several extraction from a set diameter punch and extraction re-
reasons. First, open-air drying may confound analyte covery (44, 59 ). In addition, DBS measurements can be
measurements because of contamination, especially impacted by chromatographic or matrix effects within
when the analyte of interest is DNA or an environmental the filter paper itself, which can lead to uneven spreading
contaminant (44 ). Second, drying cards under open-air of blood or distribution of analytes within a spot, de-

conditions requires extra space for drying racks and can pending on their particular physicochemical properties
be problematic in field-based collection (42 ). Third, dry- (53, 60 ). Sample heterogeneity is also a particularly
ing rates are impacted by surrounding temperature and unique issue for DBS (44, 56 ). Traditional liquid sam-
humidity conditions, which are particularly problematic ples can be easily mixed to achieve a homogenous sample
in tropical and humid environments (15, 16 ). The rate matrix, but DBS are a dried matrix, and when a portion
of drying not only impacts the ability to store samples in of a spot is punched out from filter paper, lack of homo-
a reasonable time frame, but also alters analyte measure- geneity within the spot can lead to different analyte mea-
ments, especially for metabolites and other analytes sus- surements depending on the location of the punch (66 ).
ceptible to degradation by hydrolysis, because metabo- Differential analyte stability and degradation rates,
lism and hydrolytic processes will continue within the as well as extraction efficiency, are not unique to DBS.
blood and are not quenched until moisture has been re- However, open-air drying and ambient storage are
moved from the spot (53, 54 ). It should also be noted unique and can exacerbate issues of differential analyte
that although most pathogens are inactivated by drying, stability, degradation, and extraction (42, 50 ). For exam-
some pathogens such as dengue, hepatitis B, and group A
ple, measurement of analytes susceptible to oxidation can
streptococci remain active for several days after drying
be impacted by atmospheric oxygen during drying, and
(29, 37, 58 ).
extreme temperature or humidity conditions will often
Manual DBS methods for bioanalysis are time and
have differential effects on analytes of different classes
labor intensive (59, 60 ). DBS require a series of prepara-
(65 ). A major concern involves the inability to retain and
tion steps, including punching discs from cards, elution
detect volatile organic compounds (VOCs) in DBS sam-
and extraction, filtration, and, in some instances, chem-
ples (28, 44 ). VOCs are often lost during drying, limit-
ical derivatization (13, 60 ). These steps each add cost
and complexity. For example, use of punch devices for ing the ability to measure VOCs from DBS, which in
collecting fixed diameter discs from DBS cards for anal- turns limits their utility for environmental studies (28 ).
ysis may cause contamination if devices are not ade- Beyond stability of analytes, the matrix itself can be prob-
quately cleaned between punches (i.e., carryover effects) lematic. The addition of filter paper to the matrix pres-
(61, 62 ). Some steps, like the addition of an internal ents a challenge because the filter paper can cause matrix
standard or sample dilution, may cause problems for tra- effects at the point of analysis (51, 54, 55, 67 ). For ex-
ditional samples, but they also present challenges unique ample, ion suppression is a commonly cited issue for
to DBS because of the use of a dried matrix (29 ). For DBS samples measured by mass spectrometry (68, 69 ).
example, an internal standard cannot be added to blood Another relevant issue for potential adopters is the
and homogeneously mixed before bioanalysis when sam- incomplete and emerging regulatory landscape for DBS.
pling directly by finger or heel stick, and although an The current Food and Drug Administration and Euro-
internal standard may be added to the extraction solvent, pean Medicines Agency guidelines for traditional sam-
this does not account for issues arising before extraction ples are inadequate for DBS because bioanalytic valida-
(49, 50 ). In terms of storage, because of ambient storage tion of DBS may require consideration of several
conditions, DBS are more susceptible to extreme envi- additional parameters (43 ). Added validation parameters
ronmental conditions such as high temperature and hu- may include the type of card, volume applied to filter
midity (46 ). These conditions can facilitate bacterial paper, homogeneity of spotting, hematocrit, and com-
growth or enhance the rate of analyte degradation, ren- parison with traditional samples (53, 55, 56 ). At present,
dering DBS sample results unreliable (44, 54 ). the Food and Drug Administration does not accept DBS
The most commonly cited weakness of DBS is the as a stand-alone sample and requires bridging studies for
hematocrit effect, which is the impact of varying percent- comparing DBS with traditional samples, which adds
ages of red blood cells in whole blood spotted to filter cost and labor (56 ). Lastly, there is a wide range in the
paper (63, 64 ). High or low hematocrit has 2 primary quality of validation studies and often no comparison of
issues. First, hematocrit can affect the blood-to-plasma DBS with an existing gold standard (37, 53 ).

Review
OPPORTUNITIES (1, 55, 62, 70 ). Although these methods have been

A European directive and concerns from US federal agen- shown to be analytically less sensitive than off-line man-
cies have put pressure on researchers and drug developers ual methods, their sensitivity has shown recent improve-
to comply with the “3 Rs” (i.e., reduction, refinement, ments (1 ). Researchers have also improved microsample
and replacement) in the use of animal subjects and may measurements from the data analytics side. For example,
lead to wider adoption of DBS in preclinical and toxicol- endogenous indicators such as potassium have been used
ogy studies (42 ). DBS can reduce the number of, and in DBS for estimating blood hematocrit and adjusting
stress to, animal subjects in research and development analyte measurements accordingly (63, 64 ). Further-
(27, 42 ). Other forces that may encourage DBS adop- more, as multiplex platforms such as mass spectrometry
tion are trends toward centralization of laboratories and have become more routinely used, the use of multianalyte

an increase in demand for outpatient or off-site clinical molar ratios in clinical diagnostics has shown to be an
services (40 ). As larger centralized laboratory facilities effective data analytics approach for reducing variability
adopt DBS, the quality and availability of DBS analysis and improving diagnostic performance. For example, di-
should improve. Furthermore, DBS are particularly agnosis of phenylketonuria from DBS samples in a new-
suited to nonclinic or laboratory-based settings that may born screening can be achieved by examining the relative
enable their use for off-site services such as home-based amounts of phenylalanine with those of tyrosine or leu-
sampling (5, 6 ). cine (21 ).
Traditionally, analytical instrumentation has lacked Requirements of traditional blood sampling (i.e.,
adequate sensitivity for accurate measurement of small- phlebotomy and cold chain) have often precluded the use
quantity biosamples, but recent advancements in highly of biosampling in hard-to-reach or otherwise vulnerable
sensitive instrumentation, such as LC-MS/MS and digi- populations. Use of DBS can help facilitate sampling
tal droplet quantitative PCR, have helped resolve these within these populations (7, 71 ). DBS is particularly well
issues (29, 68 ). Exponential reductions in the cost of suited for use in large complex studies for which sampling
sophisticated instruments have led to greater availability may occur at multiple sites over an extended period
of the necessary methodologies for accurate use of DBS, (5, 47 ). DBS provide a cost-effective and logistically fea-
and may also encourage adoption (52, 62 ). As interest sible method for such studies. DBS may also provide a
has continued to grow, computer-based robotic automa- sampling method for field-based forensics when proxim-
tion of DBS methods has emerged and can resolve many ity in time to events, such as driving under the influence
of the labor-intensive issues of DBS (53, 60 ). At present, or homicide, may be important for obtaining accurate
there is a range of semiautomated and fully automated measurements from blood (25, 27, 53, 54 ). DBS may
systems commercially available for DBS bioanalysis also provide an improved sample matrix for sports drug
(39, 53 ). Recent advancements in microfluidics and testing (e.g., blood doping) because a DBS microsample
nanotechnology may also provide the next generation of provides the sports community with a minimally invasive
DBS technology, and have already been applied to DBS method more conducive to collection before, during, or
for achieving high-fidelity blood droplet manipulation after an event, while also providing a longer window of
without the need for manual intervention (10, 53, 63 ). exposure (72 ). Another opportunity for DBS, in large
Such advancements can help resolve traditionally prob- part because of the suitability of the method for longitu-
lematic issues in DBS, such as measurement imprecision, dinal sampling, resides in the shift away from population-
in part because of hematocrit and chromatographic or based ranges for clinical diagnostics to more applicable
matrix effects, which in turn make it difficult to convert personal baselines that may have greater clinical relevance
DBS values to traditional plasma or serum. For example, to individual patients (73 ). Finally, DBS techniques that
membrane filtration technology has been designed for yield a stable biosample in a dried matrix under ambient
filtering out a volumetric amount of plasma from a non- storage may also be applied to a variety of other kinds of
volumetric amount of whole blood taken from a finger biological samples, such as saliva, urine, and tissue (55 ).
stick (52, 55, 69 ). Use of membrane filtration cards can
simultaneously minimize the effects of hematocrit while THREATS
also providing plasma from whole blood without the Biobanking of DBS and their suitability for DNA analy-
need for centrifugation (52, 55 ). sis present privacy and ethical dilemmas around proper
The emergence of online or direct analysis methods use of residual samples (57, 69 ). This threat is enhanced
for DBS provides several advantages over traditional by the predominant use of DBS for newborn screening,
methods, namely, the removal of the need for punch- which can be used for many other purposes (57, 74 ).
ing or elution (55, 62 ). Several technologies for online Residual samples may afford researchers a powerful tool
analysis are currently available, including desorption electro- for retrospective study. However, serious questions re-
spray ionization, direct analysis in real-time mass spectrom- main as to whether mothers could or should be ade-
etry, and paper spray mass spectrometry technologies quately consented for use of their newborn child’s sample

Review
months to years after collection. Perceived improper use among others. It is important to note, however, that al-
can lead to public outrage and loss of access to DBS though nucleic acid measurements from DBS were much
samples. For example, a settlement reached in Texas with less common than small or large molecule analyte mea-
a civil rights group led to the destruction of ⬎5 million surements, their application has been no less effective.
DBS samples (74 ). DBS has also been put forward as a Nucleic acids have been shown to be stable in DBS for
preferred sampling matrix for pediatric populations, but ⬎10 years (15, 48 ). Furthermore, improved stability of
the potential enrollment of children in research studies nucleic acids and other analytes susceptible to hydrolysis
could result in similar public outrage, particularly in the suggests that DBS samples are not just an adequate re-
event of adverse health outcomes associated with pediat- placement for plasma or serum, but in some instances,
ric clinical trials (75 ). they also may be a preferred matrix.

Another threat to DBS adoption is the dominance of An examination of the range of analytic methods
traditional samples (6, 12, 17, 24 ). Established laborato- that have been applied to DBS confirms the theory that
ries are highly automated and are optimized for plasma DBS can, in principle, be applied to measuring anything
and serum (45 ). Consequently, advantages of DBS may typically measured in liquid whole blood, plasma, or se-
be overcome by resistance from laboratories because of rum. Potential adopters may consider our analyte data-
the convenience and familiarity of traditional samples. base as a means for determining whether DBS provide a
The lack of availability of a laboratory experienced with possible solution to their respective needs, but additional
DBS samples may also constrain DBS use (17 ). If poten- inspection of the specific analytes of interest and their
tial adopters cannot readily find an experienced labora- validation of assay studies will be required before adop-
tory for bioanalysis, or if existing laboratories are unable tion. Along with each analyte in our database, we have
to handle the added workload in a timely manner, then included citations to the original research articles from
adopters may opt for traditional samples as a matter of which they were extracted, which may serve as a good first
convenience. Finally, regulatory uncertainty remains a step for those considering adoption.
serious threat to DBS adoption (47, 63 ). At present, fed- The weaknesses involved with DBS sampling can-
eral and international guidelines around DBS are lacking not be ignored but may be better understood by potential
compared with traditional samples (55, 61 ). The absence adopters by considering them in the context of their op-
of clear regulatory guidance, as well as the potential for portunities. For example, limitations in the retention and
new or unexpected regulations, will continue to constrain detection of VOCs could be obviated by identification of
widespread DBS adoption (3, 27, 55, 76 ). relevant downstream metabolites (28 ). Additionally, is-
sues in limits of detection for small-volume samples have
Discussion largely been addressed through advancements in the
quality and availability of highly sensitive analytical in-
DBS samples present potential adopters with a wide strumentation (9 ). Still, even when measured precisely,
range of options for application. In the basic sciences, the variability inherent to dried microsamples stored un-
analytes measured in DBS have been published across the der ambient conditions remains an impediment to wider
spectrum of omics-based analyses, including the genome, adoption. Current approaches to DBS rely on conversion
epigenome, transcriptome, proteome, and metabolome of measurements for single analytes to corresponding
(1, 8, 74 ). Beyond basic science, DBS have been applied plasma or serum values. However, differences between
in the field for use in public health and medicine for DBS and plasma or serum are substantial, and each pres-
measuring markers of exposure (e.g., pathogens, environ- ent the possibility of introducing bias into converted
mental toxicants), physiological response, and health measurements. Even minimal bias when introduced to a
outcomes (5, 7, 28, 29 ). From diagnosis to surveillance microsample will have a large effect on the eventual mea-
to retrospective study, the repertoire of DBS applications surement. It may be the case that clinical application of
continues to expand. DBS is better served by developing diagnostics that are
Our findings suggest a disparity between the use of especially suited to DBS rather than attempting to apply
DBS for small vs large molecule analysis. Most analytes DBS measurements to diagnostics originally developed
measured in DBS are classified as small molecule; how- for other samples.
ever, this was not unexpected, given the requirement of Our SWOT analysis identified a lack of consistency
highly sensitive analytic instrumentation such as mass in the validation studies for DBS, as well as a relatively
spectrometry for measuring small-quantity biosamples nascent regulatory landscape. However, we noted prog-
and the wide range of analytes that can be measured in a ress in the development of standards for DBS validation
single analytic run with mass spectrometry methods. Al- (12, 51, 55, 65 ). Given the current landscape, we rec-
though less common, a range of large molecules has also ommend potential adopters familiarize themselves with
been measured in DBS, including therapeutic proteins, the parameters of a quality DBS bioanalytic validation
monoclonal antibodies, and a variety of carbohydrates, (44, 61, 67 ). Although these concerns are serious, we be-

Review
lieve the literature suggests they are a self-limiting con- ples. The utility of DBS for collection of blood outside of
straint. As interest and use in the technology expand, the clinic provides a range of applications from the re-
scientific organizations and industry and regulatory agen- search laboratory to the home to the most remote envi-
cies have begun to take notice. For example, having rec- ronments on Earth. Current limitations, although
ognized the need for greater collaboration and pooling of serious, are not intractable. Issues of variability in mea-
resources, the European Bioanalysis Forum created the surements from DBS use in public health and medicine
Microsampling Topic Team, and the Global Bioanalysis can be addressed by a variety of existing and emerging
Consortium recently began investigations specifically innovations. Technological advancements in material re-
into DBS (56 ). Although the Food and Drug Adminis- quirements for DBS and data analytic approaches for
tration and other regulatory agencies do not yet accept measurement have minimized, and will likely continue

DBS as a stand-alone sampling matrix, they have encour- to, constraints around DBS adoption.
aged adopters to work closely with regulatory agencies
while conducting bridging studies between traditional
samples and DBS (65 ). In the near term, these studies Author Contributions: All authors confirmed they have contributed to
will undoubtedly add costs and complexity but will be the intellectual content of this paper and have met the following 3 require-
ments: (a) significant contributions to the conception and design, acquisi-
less necessary as regulatory agencies grow more familiar
tion of data, or analysis and interpretation of data; (b) drafting or revising
with DBS. the article for intellectual content; and (c) final approval of the published
A primary limitation of our review is attributed to article.
our methods. To survey the full landscape of a highly Authors’ Disclosures or Potential Conflicts of Interest: Upon man-
diverse field, we chose to use an SSR methodology for uscript submission, all authors completed the author disclosure form. Dis-
identifying studies for inclusion in our SWOT analysis. closures and/or potential conflicts of interest:
This choice means that advancements in the field that are Employment or Leadership: None declared.
not yet captured in broad review papers may not have Consultant or Advisory Role: None declared.
been included in our study. However, our analyte data- Stock Ownership: None declared.
base may have captured some of these studies because we Honoraria: None declared.
Research Funding: NIOSH CDC.
did not limit our literature search for the database to only
Expert Testimony: None declared.
review papers; rather, we included both review papers Patents: None declared.
and validation studies for DBS. Acknowledgments: The authors thank the Freeman Research Team
for their efforts in support of building our comprehensive analyte da-
Conclusion tabase. Specifically, we thank Lara Gaffney, Hoor Temuri, Farida Bana,
Kellie Hunn, Shiaomeng Tse, Ana Bengoechea, Steve Fischer, Dubray
Kinney, Lucas Buyon, and Connor Steele-McCutchen. We also thank
DBS provide a wide range of existing and potential ap- Dr. Margaret Taub of Johns Hopkins University Bloomberg School of
plications extending beyond the reach of traditional sam- Public Health for her assistance in analysis of the analyte database.
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State of The Science in Dried Blood Spot

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Clinical Chemistry 64:4

656–679 (2018) Review

State of the Science in Dried Blood Spots

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Of the 1636 citations identified for screening, 86 studies

Clinical Chemistry 64:4 (2018) 657

(1-(2-Morpholin-4-ylethyl)indol-3-yl)-naphthalen-1- 11-Eicosenoic acid 2,2’,3,4’,5,5’,6-Heptachlorobiphenyl

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3-Hydroxy-tetradecanoylcarnitine 4-Methylumbelliferyl ␤-D-galactopyranoside Aﬂatoxin G2

4-Aminophenyl-1-phenethylpiperidine Acetic acid Aminorex

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Arachidic acid Buprenorphine glucuronide Citalopram

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Decadienoylcarnitine Dimethoxyamphetamine Ergocalciferol

Dextrose Emtricitabine Fexinidazole

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Fluvoxamine Glycolic acid Hydroxytyrosol

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Lindane Methylcitric acid N-Acetylhexosamine

Mesocarb Monoethyl phthalate Nitisinone

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Octadecadienoylcarnitine Perchlorate Pristanic acid

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Rifapentine Suberylcarnitine Tetradecenoylcarnitine

Sodium sulﬁte Tenofovir diphosphate Uracil

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Vancomycin Acid ␣-glucosidase Anti-B-lymphocyte antigen CD20 monocodal

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Butyrylcholinesterase Chylomicron Dengue virus antibody

Catalase Coxiella burnetii antibody F-actin capping protein subunit ␤

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Fibrinopeptide A Growth hormone Herpes simplex virus 2 antibody

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Immunoreactive trypsinogen Keratin, type I cytoskeletal 10 Measles antibody

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Myosin-9 Platelet-derived growth factor B homodimer Retinal dehydrogenase 1

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Spectrin ␤, erythrocytic Transforming growth factor ␣ Uroporphyrinogen I synthetase

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cally relevant to DBS are provided in Table 2. Our

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672 Clinical Chemistry 64:4 (2018)

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3Rs, reduction, reﬁnement, and replacement.

Clinical Chemistry 64:4 (2018) 673

Table 3. Comparison of DBS with traditional liquid plasma and serum.

Characteristics DBS Traditional plasma/serum

Matrix source Capillary blood (contains interstitial Venous blood

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674 Clinical Chemistry 64:4 (2018)

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Clinical Chemistry 64:4 (2018) 675

OPPORTUNITIES (1, 55, 62, 70 ). Although these methods have been

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676 Clinical Chemistry 64:4 (2018)

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Clinical Chemistry 64:4 (2018) 677

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678 Clinical Chemistry 64:4 (2018)

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Clinical Chemistry 64:4 (2018) 679

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