The development of response surface pathway design to reduce animal numbers in toxicity studies

Dewi, Sagita; Aune, Tore; Aasen, John A.B.; Smith, A. J.; Larsen, Stig

doi:10.1186/2050-6511-15-18

Cited by 14 publications

(40 citation statements)

References 20 publications

(26 reference statements)

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“…Development of the concept in laboratory animals and computer simulations demonstrated that this is not an optimal solution. 11 Starting with a low number of subjects and increasing this number with succeeding design levels reduces the sample size without reducing the accuracy of the estimates. This procedure is not possible in the within-patient situation, but can be implemented in the …”

Section: Discussionmentioning

confidence: 99%

“…11 By starting with a low number of patients at the first design level and increasing this number with increased level, the sample size reduces without reduction in accuracy. This is possible in the between-patient RSP design using randomization.…”

Section: Rsp Designmentioning

confidence: 99%

“…For many clinicians, the methodological aim behind increasing patients with increasing design level is intuitively logical in a practical trial setting compared to the traditional equal number of included patients in each consecutive study level approach. 11 The benefit of the patient-increase procedure has been shown to optimize study design goals in lethal dose (LD) 50 studies in a laboratory setting, but has not yet been tested in dose-finding studies. However, replacement of the equal number strategy with patient-increase procedure introduces the need for randomization procedure.…”

mentioning

confidence: 99%

“…The basic RSP model was introduced in an LD 50 study requiring an odd number of mice in each design level, because LD 50 was between the escalation and de-escalation pathways. 11 The RSP methodology can, however, also be used in an even number of patient-increase procedure coupled with even or odd outcomes. Introducing odd outcomes can in this way unlock statistical strength and usability when an even number of included patients in each design level is feasible.…”

mentioning

confidence: 99%

“…Earlier UCCT using RSP methodology has focused on documentation in clinical trials without inclusion of randomization procedures, odd number of outcomes, and combinations with other classical study designs. 11 Introduction of an increasing number of included patients from one design level to the next is one way of identifying a more targeted and efficient pathway toward the area of clinical interest. For many clinicians, the methodological aim behind increasing patients with increasing design level is intuitively logical in a practical trial setting compared to the traditional equal number of included patients in each consecutive study level approach.…”

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confidence: 99%

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Randomized response surface pathway design with odd response outcomes in a Latin Square designed study

Holand¹,

Ellingsen²,

Dewi³

et al. 2017

OAJCT

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Background:Response surface pathway (RSP) design has been recently developed and described for dose-finding studies. The aim of this paper was to introduce and demonstrate additional procedures to strengthen and generalize the design and combine RSP with classical study design. Materials and methods: Nine bull calves and six heifer calves were included in an unbalanced 2 × 2 Latin Square (LSQ) designed study with large and small aperture bottle teats. The two LSQ sequences were performed with independent randomized three-level between-patient RSP design with an odd number of response classifications. The milk temperature window was 8°C-38°C with a mid temperature of 23°C. X-rays of the abdominal cavity were taken before, during, and immediately after intake of milk and recorded as "milk", "trace", or "no milk". Based on the results of the first design level, the milk temperatures for five calves in the second design level were obtained by a randomization procedure. A similar procedure was performed for seven calves in the third design level. Adjustment of the dose from one design level to the next was based on a k-adjustment factor estimated to ensure coverage of the entire predefined dose window. Results: Starting with a low number of subjects and increasing this number with increasing design levels reduces the sample size without reducing the power. The suggested randomization procedure worked as expected. No milk in Rumen was recorded and minimum milk temperature (MMT) was estimated to be ≤8°C for both teats. The odd number of response categories increases the flexibility of RSP, enabling category redefinition in hindsight from "trace" to "uncertain". After category redefinition, MMT for large bottle teat was estimated to be 14.3°C (95% confidence interval: 8.3-20.3°C), but 8°C for small. Conclusion:The suggested changes and additional procedures increase the strength and flexibility of the RSP design. Keywords: k-adjustment factor, Latin Square design, patient reduction in clinical trials, randomized response surface pathway design BackgroundDuring the first few weeks of life, milk is the primary source of nutrition for the dairy calf. Over the milk feeding period, the calf has an anatomical feature called the esophageal groove or sulcus reticuli. The groove, when activated, turns into a tube allowing the milk to pass by the reticulorumen straight into the abomasum where the milk is digested.1 Activation of the reticular groove is caused by many factors, including the smell and taste of milk, milk temperature, sucking behavior, and body posture while drinking.2 If the esophageal groove is not properly closed, milk can enter Rumen, the

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Section: Discussionmentioning

confidence: 99%

Section: Rsp Designmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Randomized response surface pathway design with odd response outcomes in a Latin Square designed study

Holand¹,

Ellingsen²,

Dewi³

et al. 2017

OAJCT

Self Cite

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Characterization of the dinophysistoxin-2 acute oral toxicity in mice to define the Toxicity Equivalency Factor

Abal

Louzao

Cifuentes

et al. 2017

Food and Chemical Toxicology

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The effect of large milk meals on digestive physiology and behaviour in dairy calves

Ellingsen

Mejdell

Ottesen

et al. 2016

Physiology & Behavior

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It is commonly believed that young calves should not be fed more than about 2l of milk per meal. If calves are fed beyond this volume, it is said that the capacity of the abomasum may be exceeded and that milk could enter the rumen. This can disturb the microbial flora/fauna of the rumen and increase the risk of indigestion, diarrhoea and reduced growth. The aim of this study was to examine the effect of large milk meals on digestive physiology and behaviour in dairy calves. Six calves (19-23days of age at the beginning of the experiment) were fed 2l of warm whole milk by teat bottle three times per day, which was the recommended Norwegian feeding regime at the time. The calves were given free access to hay, concentrates and water. During three morning feeding sessions, each separated by 48h, all calves were offered larger meals. The offered amounts were calculated according to the within patient 3-level Response Surface Pathway (RSP) design. The milk given on the three test days contained a contrast medium (barium sulphate), and the animals were radiographed before, during and immediately after intake to reveal whether milk entered the rumen. Four out of the six calves drank more than 5l in one meal and the highest voluntary intake was 6.8l in one meal (13.2% of BW). Abdominal radiographs showed that the abomasum has a large ability for distension. Milk in the rumen was not observed in any of the calves, regardless of intake. The behaviour of the calves was observed for 2h after each test session. No behaviour indicating abdominal pain or discomfort was observed regardless of intake. The results indicate that when warm whole milk is administered from a teat bottle, farmers can increase the amount of milk they offer their calves beyond the traditionally recommended portion size without risk of milk entering the rumen. Hence, farmers who want to feed their calves more milk can do so by increasing meal sizes, and not necessarily by introducing an additional meal.

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The development of response surface pathway design to reduce animal numbers in toxicity studies

Cited by 14 publications

References 20 publications

Randomized response surface pathway design with odd response outcomes in a Latin Square designed study

Randomized response surface pathway design with odd response outcomes in a Latin Square designed study

Characterization of the dinophysistoxin-2 acute oral toxicity in mice to define the Toxicity Equivalency Factor

The effect of large milk meals on digestive physiology and behaviour in dairy calves

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