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TECHNICAL NOTE: Validation of BHBCheck blood β-

hydroxybutyrate meter as a diagnostic tool for hyperketonemia.

Journal: Journal of Dairy Science

Manuscript ID JDS-17-13583.R1

Article Type: Technical Notes

Date Submitted by the Author: 09-Oct-2017

Complete List of Authors: Sailer, Kayla; University of Wisconsin-Madison, Dairy Science

Pralle, Ryan; University of Wisconsin Madison, Department of Dairy Science OLIVEIRA, RAFAEL; University of Wisconsin, Dairy Science Erb, Sophia; University of Wisconsin-Madison, Dairy Science Oetzel, Garrett; School of Veterinary Medicine, University of Wisconsin-Madison 53706, Department of Medical Sciences White, Heather; University of Wisconsin-Madison, Dairy Science

Key Words: ketosis, cowside diagnostic tool, transition cow

ScholarOne support: (434) 964 4100

Journal of Dairy Science

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Interpretive Summary 1

TECHNICAL NOTE: Validation of BHBCheck blood β-hydroxybutyrate meter as a 3

diagnostic tool for hyperketonemia in dairy cows 4

By Sailer et al. 5

Accurate cowside blood β-hydroxybutyrate detection meters are valuable tools for 6

evaluating postpartum hyperketonemia. Optimal diagnostic tools must be sensitive and 7

specific, as well as cost and labor effective to be implemented into routine testing 8

protocols. We evaluated the use of the BHBCheck blood meter for use in ketosis 9

detection compared to a laboratory assay and a previously validated meter. The 10

BHBCheck meter performed similarly to previously validated meters and had adequate 11

diagnostic accuracy for determining hyperketonemia in dairy cows. 12

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BHBCHECK METER FOR HYPERKETONEMIA DETECTION 13

TECHNICAL NOTE: Validation of the BHBCheck blood β-hydroxybutyrate meter 15

as a diagnostic tool for hyperketonemia in dairy cows 16

K. J. Sailer*, R. S. Pralle*, R. C. Oliveira*, S. J. Erb*, G. R. Oetzel†, and H. M. White*1 18

*Department of Dairy Science, University of Wisconsin-Madison, Madison, WI 53706 20

†School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706 21

1Corresponding author: Heather M. White, Department of Dairy Science, University of 22

Wisconsin-Madison, 1675 Observatory Drive, Rm 934B, Madison WI, 53706, Office: 23

608-263-7786, Fax: 608-263-7786, email: heather.white@wisc.edu 24

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ABSTRACT 25

Accurate cowside blood β-hydroxybutyrate (BHB) detection meters are valuable 26

tools for rapid diagnosis of hyperketonemia. The main objective of this study was to 27

compare the blood BHB measured in whole blood by the BHBCheck meter (PortaCheck, 28

Moorestown, NJ) to a previously validated meter, Precision Xtra meter (Abbott 29

Laboratories, Abbott Park, Illinois), and a colorimetric laboratory assay. Samples (n=426) 30

were collected from postpartum primiparous and multiparous Holstein cows (n=79 cows) 31

enrolled in one of two experiments (Exp) with different sampling schedules (Exp 1: n=39 32

cows, 58 samples; Exp 2: n=40 cows, 368 samples). In both Exp, whole blood samples 33

were collected from the coccygeal vessels after morning milking, prior to morning 34

feeding. Blood samples were used immediately for BHB quantification via the 35

BHBCheck meter and the Precision Xtra meter. Blood was also collected into evacuated 36

tubes containing no additive (Exp 1) or Potassium Oxalate/Sodium Fluoride (Exp 2), 37

which were centrifuged for serum or plasma separation and stored at -20˚C for 38

subsequent analysis. Laboratory quantification of BHB concentration was done by the 39

BHB LiquiColor Assay (EKF Diagnostics - Stanbio; Boerne, TX; certified for serum and 40

plasma). Data were analyzed by UNIVARIATE, CORR, FREQ, REG, and LOGISTIC 41

procedures of SAS 9.4. Within this sample set, average parity was 3.3 lactations and DIM 42

was 14 d. The proportion of samples classified as hyperketonemia (BHB ≥ 1.2 mmol/L) 43

was 25, 28, and 31% as determined by the colorimetric assay, BHBCheck meter, and 44

Precision Xtra meter, respectively. The correlation for BHBCheck meter BHB 45

concentration compared to the colorimetric assay concentrations was r = 0.96 with a 46

sensitivity of 91% and specificity of 93%. Correlation, sensitivity, and specificity of the 47

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Precision Xtra meter concentrations were 0.97, 98%, and 92%, respectively. Bland 48

Altman plots demonstrated minimal bias for both meters. Area under the ROC curve 49

suggests adequate diagnostic accuracy of both meters. Overall, accuracy, sensitivity, and 50

specificity of the BHBCheck meter was similar to the Precision Xtra meter and 51

laboratory assay and is appropriate for use as a cowside diagnostic test for 52

hyperketonemia in dairy cows. 53

Keywords: Ketosis, cowside diagnostic tool, transition cow 54

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TECHNICAL NOTE 55

During the postpartum period, dairy cows are at increased risk of developing 56

metabolic disorders, largely due to negative energy balance (NEB) and subsequent 57

mobilization of triglyceride (TG) from adipose tissue (Grummer, 1993; Drackley, 1999; 58

Duffield, 2000). Fates of mobilized TG within the liver include complete oxidation to 59

energy, incomplete oxidation to ketone bodies, or storage as TG (Grummer, 1993). 60

Although some peripheral tissues can use ketone bodies as an energy source, production 61

of ketone bodies beyond tissue usage results hyperketonemia (HYK). When untreated, 62

HYK is associated with negative impacts on animal health, production, and profitability 63

(Herdt, 2000; McArt et al., 2015). Hyperketonemia is defined as blood β-hydroxybutyrate 64

(BHB) ≥ 1.2 mmol/L (Iwersen et al., 2009; McArt et al., 2012b; Gordon et al., 2013; 65

2017) and the average postpartum prevalence of HYK worldwide ranges from 15 to 22%, 66

although it is highly variable by farm (Suthar et al., 2013; Chandler et al., 2015; Santschi 67

et al., 2016). The average cost per case is $289 (McArt et al., 2015); however, early 68

treatment can reduce the costs and negative outcomes (McArt et al., 2012a), making 69

detection protocols that are comprised of labor- and cost-effective diagnostics essential to 70

managing HYK. 71

Previous validation of a handheld blood ketone meter, the Precision Xtra meter 72

(Abbott Laboratories, Abbott Park, IL), provided a valuable quantitative tool for 73

diagnosing HYK using a minimally invasive blood sample, that also had greater 74

sensitivity and specificity than previously used milk and urine tests (Iwersen et al., 2009; 75

Oetzel, 2004). Recently, several additional meters have been developed and some have 76

been evaluated for potential use in bovine HYK diagnostics (Bach et al., 2016). 77

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Validation of these diagnostic tests in a controlled setting, prior to field application, is 78

essential. A relatively new meter that has not yet been validated for use in bovine HYK 79

diagnostics is the BHBCheck meter (PortaCheck, Moorestown, NJ). This meter 80

quantifies BHB in a 0.7 µL whole blood sample, which is less blood than other meters 81

which require between 0.8 to 1.5 µL of blood, and quantification is completed in under 5 82

sec, compared to other meters that average 10 sec. We hypothesized that similar to other 83

hand-held BHB diagnostic meters, the BHBCheck meter would provide adequate 84

accuracy for HYK diagnostics in dairy cattle. The objectives of this study were 1) to 85

determine the efficacy of the BHBCheck meter as a cowside BHB monitoring device by 86

validating it against a colorimetric laboratory assay and 2) to compare the BHBCheck 87

meter to an industry standard cowside meter (Precision Xtra). 88

We conducted two animal experiments that were approved by the University of 89

Wisconsin-Madison College of Agricultural and Life Sciences Animal Care and Use 90

Committee (protocol numbers A05467 and A01569). For both experiments (Exp), blood 91

was collected from Holstein cows immediately following morning milking and prior to 92

feeding. The samples from Exp 1 were collected from 39 primiparous and multiparous 93

cows between 4 and 18 DIM during twice weekly sampling on a privately-owned dairy in 94

south-central Wisconsin from May to June 2016. Experiment 1 was intended to provide 95

a balanced dataset of an equal number of samples that were above and below the 1.2 96

mmol/L HYK threshold. This was accomplished by collecting whole blood from cows 97

between 4 and 18 DIM into evacuated collection tubes without additives and immediately 98

analyzing blood using the Precision Xtra test. When a cow with HYK was identified, she 99

was included in the study along with the next cow that was negative for HYK. Whole 100

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blood samples were also analyzed using the BHBCheck meter. Samples were collected 101

over several farm visits and some cows contributed more than one sample to the dataset. 102

Although the balanced design in Exp 1 resulted in a nonrepresentative sample set relative 103

to the population prevalence, it avoided having a sample set with a minimal proportion of 104

samples above the 1.2 mmol/L threshold. Whole blood tubes were then centrifuged 105

(2,500 x g, 15°C, 15 minutes) and serum was aliquoted and stored into 1.5 mL 106

microtubes at -20°C until subsequent analysis. Experiment 2 was conducted at the 107

University of Wisconsin-Madison Dairy Cattle Center from May to October 2016. Blood 108

samples were collected from 40 multiparous cows between 1 and 45 DIM into an 109

evacuated tube without additives, and into an evacuated tube containing potassium 110

oxalate and sodium fluoride. Whole blood from the tube without additives was 111

immediately analyzed on the BHBCheck and Precision Xtra meter. The tube containing 112

potassium oxalate and sodium fluoride was centrifuged (2,000 x g, 4°C, 15 minutes) and 113

plasma was aliquoted into 1.5 mL microtubes, and stored at -20°C for subsequent 114

analysis. 115

Serum samples from Exp 1 and plasma samples from Exp 2 were analyzed using the 116

LiquiColor colorimetric assay (EKF Diagnostics - Stanbio, Boerne, TX; certified for 117

serum and plasma collected with EDTA, heparin, or sodium fluoride) per the 118

manufacturer’s protocol. Samples were quantified in duplicate and samples with intra-119

assay CV greater than 10% were reanalyzed. The inter-assay CV of the laboratory assay 120

was 6.7%. Sample BHB concentration determined by the laboratory assay served as the 121

“gold standard” BHB concentration for statistical analysis. 122

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Data analysis was completed in SAS 9.4 (Cary, NC). Descriptive statistics were 123

analyzed by PROC UNIVARIATE. Residuals were produced by PROC REG with 124

colorimetric laboratory assay BHB as the dependent variable and BHBCheck or Precision 125

Xtra meter quantified BHB as the independent variable. Pearson correlations between the 126

BHB concentration determined by both meters and by the colorimetric assay were 127

analyzed by PROC CORR. In order to account for correlation among residual errors due 128

to the repeated measures on the experimental unit (cow) across time, different error 129

structures (i.e. compound symmetry, first order auto-regressive, and spatial power) were 130

tested using PROC MIXED. A log-likelihood ratio tests was performed between 131

the repeated measure models and the null model and indicated accounting for repeated 132

structure of the data did not significantly alter model fit. Therefore, analysis of the data 133

continued without accounting for repeated measures. Sensitivity and specificity were 134

calculated by PROC FREQ. Receiver operating characteristic (ROC) curves and 135

associated area under the curve were determined by PROC LOGISTIC. Results for Exp 1 136

and 2 are provided both separately, and combined, in order to provide the diagnostic 137

accuracy of the meters in two sample sets with different proportion of samples greater 138

than or equal to 1.2 mmol/L. 139

Demographics of the samples from Exp 1, 2, and Overall are provided in Table 1. 140

Samples were collected from a total of 79 Holstein cows with an average parity of 3.3 ± 141

0.1 and average DIM of 14.3 ± 0.6 across the two experiments (Table 1). The mean BHB 142

was 1.3 ± 0.12, 1.0 ± 0.03, and 1.0 ± 0.03 mmol/L for samples from Exp 1, 2, and 143

Overall, respectively. The range of BHB was from 0.3 to 5.4 mmol/L across all samples, 144

as determined by colorimetric laboratory assay. 145

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Proportion of samples with BHB ≥ 1.2 mmol/L, as determined by the colorimetric 146

assay were 50% for Exp 1, 21% for Exp 2, and 25% for the Overall dataset. Use of either 147

meter to calculate the proportion of samples with BHB ≥ 1.2 mmol/L resulted in slight 148

overestimations in Exp 2 and Overall for the BHBCheck (50%, 25%, and 28% for Exp 1, 149

Exp 2, and Overall) and in Exp 1, Exp 2, and Overall for the Precision Xtra (55%, 27%, 150

and 31% for Exp 1, Exp 2, and Overall). This overestimation highlights the possibility of 151

false positives when using a cowside BHB meter to diagnose HYK, and would result in 152

treating a small number of cows that do not have blood BHB ≥ 1.2 mmol/L per the 153

laboratory assay. Treating false positives does have a cost associated with it dependent on 154

the disease and treatment; however, in the case of HYK, the cost of treatment is relatively 155

low compared with the cost of an untreated HYK case (McArt et al., 2015). 156

Concentrations of BHB as determined by the BHBCheck or Precision Xtra meter were 157

correlated (P<0.001) with concentrations determined by the colorimetric laboratory 158

assay. Correlation coefficients were 0.98 for both meters compared with the laboratory 159

assay in Exp 1. The correlation coefficients were 0.96 and 0.97, for the BHBCheck and 160

Precision Xtra meter, respectively, in Exp 2 and the Overall dataset. Interestingly, the 161

correlation between the two meters was 0.98 for Exp 1, 2, and Overall. Fit statistics for 162

linear regression analysis of the BHBCheck and laboratory assay resulted in an r2 and 163

RMSE of 0.96 and 0.17 for Exp 1, 0.92 and 0.19 for Exp 2, and 0.93 and 0.19 Overall 164

(Figure 1). 165

Linear regression analysis of the Precision Xtra meter compared with the laboratory 166

assay resulted in an r2 and RMSE of 0.97 and 0.17 for Exp 1, 0.94 and 0.17 for Exp 2, 167

and 0.94 and 0.17 Overall (Figure 1). Bland Altman plots (Bland and Altman, 1986) 168

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show test agreement (Figure 2) and demonstrate minimal bias for both meters (-0.05 and 169

-0.09 for the BHBCheck and Precision Xtra meter, respectively, compared with the 170

laboratory assay). Bias of -0.05 and -0.09 would not influence diagnostic ability of the 171

test cowside and is consistent with minimal bias previously observed with cowside BHB 172

diagnostic tests (Bach et al., 2016). 173

Although correlation and regression methods are valuable indicators of a diagnostic 174

tool’s quantitative accuracy, it is equally important to evaluate the sensitivity and 175

specificity of the meters at relevant diagnostic cutoff concentrations. Sensitivity and 176

specificity of the Precision Xtra meter was 98 and 92% at 1.2 mmol/L for the Overall 177

dataset in the current study (Table 2), which is consistent with previous validation of this 178

meter (Iwersen et al., 2009; Voyvoda and Erdogan, 2010; Bach et al., 2016). Similarly, 179

the BHBCheck meter had a sensitivity and specificity of 91 and 93% at the 1.2 mmol/L 180

threshold. Sensitivity and specificity were greater in Exp 2 than Exp 1, likely due to the 181

difference in sample size. Although both sensitivity and specificity are important 182

indicators of a diagnostic tool, sensitivity is arguably more valuable for subclinical 183

disorders with low-cost and low-risk treatments. Subclinical animals would fail to be 184

diagnosed if missed by the diagnostic test, given the lack of obvious disease symptoms. 185

In the case of HYK, the treatment cost of treatment is relatively inexpensive compared to 186

the cost of an untreated case (McArt et al., 2015); thus, adequate sensitivity of a potential 187

cowside diagnostic tool is important to consider (Bach et al., 2016). 188

Determination of the area under the ROC curve is an objective means of evaluating 189

the overall validity of a diagnostic tool (Šimundić, 2009). Receiver operating 190

characteristic curves represent the paired sensitivity and specificity for each cutoff, and 191

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when plotted, the resulting curve allows for estimation of the discriminative power of a 192

test. Areas under the ROC between 0.9 and 1.0 represent “excellent” diagnostic accuracy 193

according to ROC diagnostic categories (Šimundić, 2009). In the current study, area 194

under the ROC for the BHBCheck meter was 0.98, 0.98, and 0.98 for Exp 1, Exp 2, and 195

Overall. The area under the ROC curve for the Precision Xtra meter was 0.98, 0.99, and 196

0.99 for Exp 1, Exp 2, and Overall. This evaluation indicates that both the Precision Xtra 197

and BHBCheck meters portray adequate diagnostic abilities. 198

Overall, performance of the Precision Xtra meter within the current study was 199

consistent with previous studies (Iwersen et al., 2009; Bach et al., 2016). The Precision 200

Xtra meter has been previously validated and has set the expectation for sensitivity and 201

specificity for a cowside BHB meter. While it is advantageous to have several diagnostic 202

options, diagnostic tools need to be evaluated to ensure test accuracy. Within the current 203

study, the BHBCheck meter performed similarly to the Precision Xtra meter in this study 204

and to other meters previously examined (Bach et al., 2016; Iwersen et al., 2009; 205

Voyvoda and Erdogan, 2010). Both meters were consistent with expectations of a 206

diagnostic tool and displayed adequate diagnostic accuracy. We conclude that the 207

BHBCheck meter is an accurate and valuable option for use in HYK detection protocols. 208

ACKNOWLEDGEMENTS 210

This research was partially funded by gifts from the Wisconsin Alumni Research 211

Foundation. BHBCheck meters and strips were provided by PortaCheck. The authors 212

would like to thank the University of Wisconsin-Madison Dairy Cattle Center staff as 213

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well as the owner and herdsman of the privately-owned dairy for their cooperation during 214

this research project. 215

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REFERENCES 217

Bach, K. D., W. Heuwieser, and J. A. A. McArt. 2016. Technical note: Comparison of 4 218 electronic handheld meters for diagnosing hyperketonemia in dairy cows. J. Dairy 219 Sci. 99:9136–9142. doi:10.3168/jds.2016-11077. 220

Bland, J. M., and D. G. Altman. 1986. Statistical methods for assessing agreement 221 between two methods of clinical measurement. Lancet. 1:307-310. 222

Chandler, T. L., R. S. Pralle, G. R. Oetzel, R. H. Fourdraine, and H. M. White. 2015. 223 Development of a ketosis prevalence tool in Holstein dairy cows based on milk 224 component data and cow test-day information. J. Dairy Sci. Vol 98, Suppl 2. 225

Drackley, J. K. 1999. ADSA Foundation Scholar Award. Biology of dairy cows during 226 the transition period: the final frontier? J. Dairy Sci. 82:2259–2273. 227 doi:10.3168/jds.S0022-0302(99)75474-3. 228

Duffield, T. 2000. Subclinical ketosis in lactating dairy cattle. Vet. Clin. North Am. Food 229 Anim. Pract. 16:231–253. 230

Gordon, J. L., S. J. Leblanc, and T. F. Duffield. 2013. Ketosis treatment in lactating dairy 231 cattle. Vet. Clin. North Am. Food Anim. Pract. 29:433–445. 232 doi:10.1016/j.cvfa.2013.03.001. 233

Gordon, J. L., T. F. Duffield, T. H. Herdt, D. F. Kelton, L. Neuder, and S. J. LeBlanc. 234 2017. Effects of a combination butaphosphan and cyanocobalamin product and 235 insulin on ketosis resolution and milk production. J. Dairy Sci. 100:2954–2966. 236 doi:10.3168/jds.2016-11925. 237

Grummer, R. R. 1993. Etiology of Lipid-Related Metabolic Disorders in Periparturient 238 Dairy Cows. J. Dairy Sci. 76:1–15. 239

Herdt, T. H. 2000. Ruminant adaptation to negative energy balance. Influences on the 240 etiology of ketosis and fatty liver. Vet. Clin. North Am. Food Anim. Pract. 16:215–241 230. doi: 10.1016/S0749-0720(15)30102-X. 242

Iwersen, M., U. Falkenberg, R. Voigtsberger, D. Forderung, and W. Heuwieser. 2009. 243 Evaluation of an electronic cowside test to detect subclinical ketosis in dairy cows. J. 244 Dairy Sci. 92:2618–2624. doi:10.3168/jds.2008-1795. 245

McArt, J. A. A., D. V. Nydam, and G. R. Oetzel. 2012a. A field trial on the effect of 246 propylene glycol on displaced abomasum, removal from herd, and reproduction in 247 fresh cows diagnosed with subclinical ketosis. J. Dairy Sci. 95:2505–2512. 248 doi:10.3168/jds.2011-4908. 249

McArt, J. A. A., D. V. Nydam, and G. R. Oetzel. 2012b. Epidemiology of subclinical 250 ketosis in early lactation dairy cattle. J. Dairy Sci. 95:5056–5066. 251 doi:10.3168/jds.2012-5443. 252

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McArt, J. A. A., D. V. Nydam, and M. W. Overton. 2015. Hyperketonemia in early 253 lactation dairy cattle: A deterministic estimate of component and total cost per case. J. 254 Dairy Sci. 98:2043–2054. doi:10.3168/jds.2014-8740. 255

Oetzel, G. R. 2004. Monitoring and testing dairy herds for metabolic disease. Vet. Clin. 256 North Am. Food Anim. Pract. 20:651–674. doi:10.1016/j.cvfa.2004.06.006. 257

Santschi, D. E., R. Lacroix, J. Durocher, M. Duplessis, R. K. Moore, and D. M. Lefebvre. 258 2016. Prevalence of elevated milk β-hydroxybutyrate concentrations in Holstein 259 cows measured by Fourier-transform infrared analysis in Dairy Herd Improvement 260 milk samples and association with milk yield and components. J. Dairy Sci. 99:9263–261 9270. doi:10.3168/jds.2016-11128. 262

Šimundić, A. 2009. Measures of diagnostic accuracy: basic definitions. eJIFCC. 19:203-263 211. 264

Suthar, V. S., J. Canelas-Raposo, A. Deniz, and W. Heuwieser. 2013. Prevalence of 265 subclinical ketosis and relationships with postpartum diseases in European dairy 266 cows. J. Dairy Sci. 96:2925–2938. doi:10.3168/jds.2012-6035. 267

Voyvoda, H., and H. Erdogan. 2010. Use of a hand-held meter for detecting subclinical 268 ketosis in dairy cows. Res.Vet. Sci. 89:344–351. doi:10.1016/j.rvsc.2010.04.007. 269

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Table 1. Demographics of samples from experiment (Exp) 1 (collected between 4 and 18 271

DIM), Exp 2 (collected between 1 and 45 DIM), and Overall used to evaluate the 272

cowside blood β-hydroxybutyrate meters1 compared with a colorimetric laboratory 273

assay2. 274

Exp 1 Exp 2 Overall

Unique cows 39 40 79 Samples 58 368 426 Cow variables

parity ± SE 2.7 ± 0.18 3.3 ± 0.08 3.3 ± 0.08

DIM ± SE 10.2 ± 0.56 15.1 ± 0.66 14.3 ± 0.58

BHB3, mmol/L

mean ± SE 1.3 ± 0.12 1.0 ± 0.03 1.0 ± 0.03

median 1.2 0.7 0.8 min 0.3 0.3 0.3

max 3.9 5.4 5.4 275

1BHBCheck meter (PortaCheck, Moorestown, NJ) and Precision Xtra meter (Abbott 276

Laboratories, Abbott Park, Illinois). 277

2LiquiColor colorimetric assay (EKF Diagnostics - Stanbio, Boerne, TX). 278

3As quantified by the colorimetric laboratory assay. 279

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Table 2. Sensitivity and specificity of cowside blood β-hydroxybutyrate meters1 to 283

correctly identify samples as greater than or equal to 1.2 mmol/L, based on a colorimetric 284

laboratory assay2 within experiment (Exp) 1 (collected between 4 and 18 DIM), Exp 2 285

(collected between 1 and 45 DIM), and Overall. 286

Exp 1 Exp 2 Overall Samples 58 368 426 Samples ≥ 1.2 mmol/L 29

BHBCheck Sens, % 89 [71,98] 3

91 [84,96]

Spec, % 84 [66,95]

93 [89,95]

93 [89,95] Precision Xtra

Sens, % 100 [87,100] 97 [91,99] 98 [93,99] Spec, % 84 [66,95] 92 [88,95] 92 [88,94]

1BHBCheck meter (PortaCheck, Moorestown, NJ) and Precision Xtra meter (Abbott 288

Laboratories, Abbott Park, Illinois). 289

2LiquiColor colorimetric assay (EKF Diagnostics - Stanbio, Boerne, TX). 290

3 [95% CI] 291

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Sailer Figure 1. Linear regression of blood β-hydroxybutyrate (BHB) concentrations 293

quantified by BHBCheck (PortaCheck, Moorestown, NJ; left panels) and Precision Xtra 294

meter (Abbott Laboratories, Abbott Park, Illinois; right panels) compared with a 295

colorimetric laboratory assay (LiquiColor colorimetric assay; EKF Diagnostics - Stanbio, 296

Boerne, TX) within experiment (Exp) 1 (top panels; 58 samples, collected between 4 and 297

18 DIM), Exp 2 (368 samples, collected between 1 and 45 DIM), and Overall (bottom 298

panels). 299

Sailer Figure 2. Differences of blood BHB concentrations determined in 426 samples 301

(collected between 1 and 45 DIM across two studies) by a laboratory assay (LiquiColor 302

colorimetric assay; EKF Diagnostics - Stanbio, Boerne, TX) and BHBCheck 303

(PortaCheck, Moorestown, NJ; top panel) or Precision Xtra meter (Abbott Laboratories, 304

Abbott Park, Illinois; middle panel) and between the two meters (bottom panel). 305

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308 Sailer Figure 1. 309 310 311

312 313 314

BHBCheck BHB, mmol/L Precision Xtra BHB, mmol/L

r = 0.98

r = 0.96

r = 0.98

r = 0.97

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Sailer Figure 2. 315

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Average BHB for Assay and BHBCheck, mmol/L

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Average BHB for Assay and Precision Xtra, mmol/L

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Average BHB for PrecisionXtra and BHBCheck, mmol/L

+2 SD = 0.34

-2 SD = -0.44

mean = -0.05

+2 SD = 0.33

-2 SD = -0.51

mean = -0.09

+2 SD = 0.38 mean = 0.04

-2 SD = -0.29

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