scholarly journals Determining organ weight toxicity with Bayesian causal models: Improving on the analysis of relative organ weights

2019 ◽  
Author(s):  
Stanley E. Lazic ◽  
Elizaveta Semenova ◽  
Dominic P. Williams
Keyword(s):  
Body Weight ◽  
Multiple Testing ◽  
Weight Ratio ◽  
Organ Damage ◽  
Organ Weight ◽  
Analysis Of Covariance ◽  
Toxicity Tests ◽  
Weight Changes ◽  
Organ Weights ◽  
Chemically Induced

AbstractRegulatory authorities require animal toxicity tests for new chemical entities. Organ weight changes are accepted as a sensitive indicator of chemically induced organ damage, but can be difficult to interpret because changes in organ weight might reflect chemically-induced changes in overall body weight. A common solution is to calculate the relative organ weight (organ to body weight ratio), but this inadequately controls for the dependence on body weight – a point made by statisticians for decades, but which has not been widely adopted. The recommended solution is an analysis of covariance (ANCOVA), but it is rarely used, possibly because both the method of statistical correction and the interpretation of the output may be unclear to those with minimal statistical training. Using relative organ weights can easily lead to incorrect conclusions, resulting in poor decisions, wasted resources, and an ethically questionable use of animals. We propose to cast the problem into a causal modelling framework as it directly assesses questions of scientific interest, the results are easy to interpret, and the analysis is simple to perform with freely available software. Furthermore, by taking a Bayesian approach we can model unequal variances, control for multiple testing, and directly provide evidence of safety.

scholarly journals The fallacy of ratio correction to address confounding factors

2012 ◽  
Vol 46 (3) ◽  
pp. 245-252 ◽  
Author(s):  
Natasha A Karp ◽  
Anne Segonds-Pichon ◽  
Anna-Karin B Gerdin ◽  
Ramiro Ramírez-Solis ◽  
Jacqueline K White
Keyword(s):  
Body Weight ◽  
Gene Knockout ◽  
Weight Ratio ◽  
The Body ◽  
Analysis Of Covariance ◽  
Biological Research ◽  
Confounding Factors ◽  
Weight Changes ◽  
Ratio Correction

Scientists aspire to measure cause and effect. Unfortunately confounding variables, ones that are associated with both the probable cause and the outcome, can lead to an association that is true but potentially misleading. For example, altered body weight is often observed in a gene knockout; however, many other variables, such as lean mass, will also change as the body weight changes. This leaves the researcher asking whether the change in that variable is expected for that change in weight. Ratio correction, which is often referred to as normalization, is a method used commonly to remove the effect of a confounding variable. Although ratio correction is used widely in biological research, it is not the method recommended in the statistical literature to address confounding factors; instead regression methods such as the analysis of covariance (ANCOVA) are proposed. This method examines the difference in means after adjusting for the confounding relationship. Using real data, this manuscript demonstrates how the ratio correction approach is flawed and can result in erroneous calls of significance leading to inappropriate biological conclusions. This arises as some of the underlying assumptions are not met. The manuscript goes on to demonstrate that researchers should use ANCOVA, and discusses how graphical tools can be used readily to judge the robustness of this method. This study is therefore a clear example of why assumption testing is an important component of a study and thus why it is included in the Animal Research: Reporting of In Vivo Experiment (ARRIVE) guidelines.

Relationships Between Organ Weight and Body/Brain Weight in the Rat: What Is the Best Analytical Endpoint?

2004 ◽  
Vol 32 (4) ◽  
pp. 448-466 ◽  
Author(s):  
Steven A. Bailey ◽  
Robert H. Zidell ◽  
Richard W. Perry
Keyword(s):  
Body Weight ◽  
Weight Ratio ◽  
Organ Weight ◽  
Brain Weight ◽  
Analysis Of Covariance ◽  
Alternative Analysis ◽  
Treatment Groups ◽  
Using Data ◽  
The Relationship ◽  
Target Organ Toxicity

Analysis of organ weight in toxicology studies is an important endpoint for identification of potentially harmful effects of chemicals. Differences in organ weight between treatment groups are often accompanied by differences in body weight between these groups, making interpretation of organ weight differences more difficult. Using data from control rats that were part of 26 toxicity studies conducted under similar conditions, we have evaluated the relationship between organ weight and body/brain weight to determine which endpoint (organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio) is likely to accurately detect target organ toxicity. This evaluation has shown that analysis of organ-to-body weight ratios is predictive for evaluating liver and thyroid gland weights, and organ-to-brain weight ratios is predictive for evaluating ovary and adrenal gland weights. Brain, heart, kidney, pituitary gland, and testes weights are not modeled well by any of the choices, and alternative analysis methods such as analysis of covariance should be utilized.

THE EFFECT OF COLD ACCLIMATION ON THE SIZE OF ORGANS AND TISSUES OF THE RAT, WITH SPECIAL REFERENCE TO MODES OF EXPRESSION OF RESULTS

1958 ◽  
Vol 36 (2) ◽  
pp. 209-216 ◽  
Author(s):  
O. Heroux ◽  
N. T. Gridgeman
Keyword(s):  
Experimental Data ◽  
Body Weight ◽  
Special Reference ◽  
Cold Acclimation ◽  
Muscle Mass ◽  
Cold Adaptation ◽  
Organ Weight ◽  
Organ Weights ◽  
White Rats ◽  
Body Weights

In experiments in which two groups of animals of different mean body weight are compared, individual organ weights of the animals can be expressed as absolute weights, as fractional weights, or as absolute weights statistically regressed onto constant body weights. The second, and commonest, mode of expression involves the assumption that the part is directly proportional to the whole, and this is shown to be unlikely for all organs except the muscle mass. Practical as well as theoretical justifications for the use of regressed weights (which utilize the actual slope of the line relating the organ weight to the whole) are given.The experimental data are from white rats kept for 4 weeks in a warm (30 °C.) or a cold (6 °C.) environment. It is shown that cold adaptation had no effect on brain, genitals, and lung weights, but that it reduced the growth of muscle, pelt, fat, skeleton, spleen, and thymus, and that it hypertrophied the liver, intestine, kidney, heart, and adrenals. Apparently cold acclimated rats are smaller than the controls mainly because they have a smaller muscle mass.

Transgenic Expression of Human Platelet FcγRIIA (CD32A) in Mice Does Not Affect the Thrombocytopenia Associated with WASp Deficiency.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1106-1106
Author(s):  
Michael P. Marchetti ◽  
Francois Maignen ◽  
Herve Falet
Keyword(s):  
Flow Cytometry ◽  
Body Weight ◽  
Platelet Count ◽  
Weight Ratio ◽  
Analysis Of Covariance ◽  
Spleen Weight ◽  
Severe Thrombocytopenia ◽  
Body Weight Ratio ◽  
Igg Antibody ◽  
Normal Platelet

Abstract Wiskott-Aldrich Syndrome (WAS) is an X-linked hematopoietic disorder that is characterized by immune deficiency, eczema and severe thrombocytopenia with small platelets. Platelets isolated from WAS patients are cleared rapidly from the circulation when transfused autologously. However, the role of WASp, the protein mutated or absent in WAS, is unclear since platelets isolated from WAS patients function normally. WASp knockout (KO) mice only have a mild thrombocytopenia. Because 1) human, but not mouse platelets express the Fc receptor for IgGs, FcγRIIA (CD32A), and 2) platelet-associated IgGs (PAIgGs) are often observed in WAS patients, we sought to determine whether FcγRIIA expression in humans was involved in the severe thrombocytopenia associated with WAS. WASp KO mice expressing human FcγRIIA on the surface of their platelets were generated by breeding female mice carriers for WASp deficiency with heterozygous FcγRIIA transgenic (TG) males. A total of 221 offsprings were obtained, of which only 97 were males. WASp KO / FcγRIIA TG males were a minority, with a total of 19 animals, compared to 24 WASp WT / FcγRIIA WT, 30 WASp WT / FcγRIIA TG and 24 WASp KO / FcγRIIA WT males. WASp KO / FcγRIIA WT and WASp KO / FcγRIIA TG males had about 70% of normal platelet count compared to WASp WT / FcγRIIA WT and WASp WT / FcγRIIA TG mice (Table 1). Thus, FcγRIIA expression did not affect the thrombocytopenia associated with WASp deficiency. PAIgGs were not detected on the surface of WASp KO / FcγRIIA TG platelets, as evaluated by flow cytometry using an anti-mouse IgG antibody. Spleen weight was increased in WASp KO / FcγRIIA TG compared to WASp WT / FcγRIIA WT and WASp WT / FcγRIIA TG males, but similar to that of WASp KO / FcγRIIA WT males (Table 1). Age of the mice was not involved since similar results were obtained with 6-, 12- or 24-weeks old mice. However, an increased population of macrophages appeared in the spleen of mice lacking WASp as they aged, as evidenced by flow cytometry using anti-mouse Mac-1 (CD11b) and Gr-1 (Ly-6G) antibodies. Our data indicate that expression of platelet FcγRIIA alone does not explain the difference observed between the severe thrombocytopenia of WAS patients and the mild thrombocytopenia of WASp KO mice. WASp deficiency may affect the surface organization of platelets such that clearance is accelerated by spleen macrophages. Table 1. Platelet count and spleen/body weight ratio in WASp KO / FcγRIIA TG mice relative to controls. WASp WT / FcγRIIA WT WASp WT / FcγRIIA TG WASp KO / FcγRIIA WT WASp KO / FcγRIIA TG Results represent mean ± SD. The statistical analysis was performed by analysis of covariance (ANCOVA) with an adjustment on the spleen/body weight ratio. The family error rate for the multiple comparisons was maintained below 0.05 (Sidak method). Platelet count (× 103/μl) 998 ± 145 963 ± 172 677 ± 147 682 ± 120 p < 10−7 Spleen/body weight ratio (mg/g) 2.9 ± 0.6 2.9 ± 0.5 4.1 ± 1.6 3.8 ± 1.8 p < 0.05 Number of males (adjusted) 31 35 30 30

scholarly journals Safety Evaluation of Aqueous Extract of Garcinia Kola Seeds in Male Wistar Rats

2016 ◽  
Vol 10 (1) ◽  
pp. 41-47
Author(s):  
Musa Toyin Yakubu ◽  
◽  
Ayodeji Luqman Quadri ◽  
Keyword(s):  
Body Weight ◽  
Aqueous Extract ◽  
Safety Evaluation ◽  
Weight Ratio ◽  
Organ Damage ◽  
Male Rats ◽  
Gamma Glutamyl Transferase ◽  
Body Weight Ratio ◽  
Garcinia Kola ◽  
Glutamyl Transferase

Background: Garcinia kola seed is consumed indiscriminately in Nigeria without recourse to its potential toxicity. Therefore, this study was aimed at assessing the toxicity of the aqueous extract of G. kola seeds on selected tissues of male rats. Methods: Thirty male rats (215.00 ± 18.58 g) were assigned into four groups: A, B, C and D which received 0.5 ml of distilled water, 25, 50 and 100 mg/kg body weight of the extract respectively, once daily for 7 days. Biochemical indices of organ damage and toxicity were determined using standard methods. Results: The extract significantly (P<0.05) increased the testes-body weight ratio, activities of testicular alkaline phosphatase (ALP), heart, testes and serum gamma glutamyl transferase (GGT) activity, serum concentrations of uric acid, K+, creatinine and PO43-. The liver-body weight ratio, activities of kidney and serum ALP, liver, heart and serum alanine and aspartate aminotransferases (ALT and AST), serum and testicular acid phosphatase (ACP), concentrations of serum albumin, globulin, urea, Na+ , HCO3-, conjugated and total bilirubin were reduced. The heart- and kidney-body weight ratios and liver ALP were not significantly (P>0.05) altered. Conclusion: The treatment related alterations in the present study indicates that the aqueous extract of G. kola seeds at the doses of 25, 50 and 100 mg/kg body weight caused functional toxicity to the organs of the animals and thus not safe as an oral remedy.

scholarly journals Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice

2018 ◽  
Vol 10 (02) ◽  
pp. 176-187 ◽  
Author(s):  
K. Neier ◽  
D. Cheatham ◽  
L. D. Bedrosian ◽  
D. C. Dolinoy
Keyword(s):  
Dna Methylation ◽  
Body Weight ◽  
Coat Color ◽  
Epidemiological Studies ◽  
Weight Changes ◽  
Organ Weights ◽  
Additional Layer ◽  
Specific Effects ◽  
Intracisternal A Particle ◽  
Developmental Exposures

AbstractDevelopmental exposure to phthalates has been implicated as a risk for obesity; however, epidemiological studies have yielded conflicting results and mechanisms are poorly understood. An additional layer of complexity in epidemiological studies is that humans are exposed to mixtures of many different phthalates. Here, we utilize an established mouse model of perinatal exposure to investigate the effects of three phthalates, diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP) and dibutyl phthalate (DBP), on body weight and organ weights in weanling mice. In addition to individual phthalate exposures, we employed two mixture exposures: DEHP+DINP and DEHP+DINP+DBP. Phthalates were administered through phytoestrogen-free chow at the following exposure levels: 25 mg DEHP/kg chow, 25 mg DBP/kg chow and 75 mg DINP/kg chow. The viable yellow agouti (Avy) mouse strain, along with measurement of tail DNA methylation, was used as a biosensor to examine effects of phthalates and phthalate mixtures on the DNA methylome. We found that female and male mice perinatally exposed to DINP alone had increased body weights at postnatal day 21 (PND21), and that exposure to mixtures did not exaggerate these effects. Females exposed to DINP and DEHP+DINP had increased relative liver weights at PND21, and females exposed to a mixture of DEHP+DINP+DBP had increased relative gonadal fat weight. Phthalate-exposedAvy/aoffspring exhibited altered coat color distributions and altered DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. These findings provide evidence that developmental exposures to phthalates influence body weight and organ weight changes in early life, and are associated with altered DNA methylation at IAPs.

scholarly journals Acute and 28-days subacute toxicity studies of Gαq-RGS2 signaling inhibitor

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Jayesh V. Beladiya ◽  
Anita A. Mehta
Keyword(s):  
Body Weight ◽  
Oral Dose ◽  
Oral Administration ◽  
Single Oral Dose ◽  
Hematological Parameters ◽  
Weight Ratio ◽  
Repeated Administration ◽  
Organ Damage ◽  
Synthetic Compound ◽  
Single Oral Administration

Abstract Background The aim of study was to evaluate the single oral dose and 28 day repeated oral administration toxicity profile of the synthetic compound Gαq-RGS2 signaling inhibitor, (1-(5-chloro-2-hydroxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1 H-1,2,4-triazol-5(4 H)-one) as per OECD guideline 425 (2008a) and 407 (2008b), respectively. Results In acute toxicity study, a single oral dose administration of Gαq-RGS2 signaling inhibitor did not show any mortality at doses of 5, 50, 300 and 2000 mg/kg within 24 h and 14 days. The treatment of Gαq-RGS2 signaling inhibitor at dose 10 and 100 mg/kg for 28 days did not show any mortality, significant changes in the increase of body weight, various organ damage markers, hematological parameters, relative organ/body weight ratio and microscopic anatomical texture of essential organs as compared to vehicle and normal control. Conclusions A single oral administration of Gαq-RGS2 signaling inhibitor up to dose of 2000 mg/kg in mice and repeated administration of Gαq-RGS2 signaling inhibitor at higher dose 100 mg/kg for 28 days in the rats is safe.

scholarly journals The variability of organ weight background data in rats

1993 ◽  
Vol 27 (1) ◽  
pp. 65-72 ◽  
Author(s):  
Ephraim Gur ◽  
Trevor Waner
Keyword(s):  
Organ Weight ◽  
Analysis Of Covariance ◽  
Sprague Dawley ◽  
Control Groups ◽  
Organ Weights ◽  
Concurrent Control ◽  
Fields Of Study ◽  
Sprague Dawley Rats ◽  
Background Data ◽  
Weight Data

The variability of organ weight data in a series of 5 control groups of Sprague-Dawley rats was studied. Differences in body weight and organ weight data were detected between the studies. Attempts to reduce the variability of organ weights by using analysis of covariance or organ to brain weight ratios were only partially successful. Factors which may influence animals under controlled conditions and result in variability between studies are discussed. It is concluded that caution is needed when considering the use of organ weight background data as a means of comparison. The findings are in agreement with other fields of study in toxicological testing, and emphasize the importance of using a concurrent control for the purpose of comparison of data.

ORGAN WEIGHT – BODY WEIGHT RELATIONS IN THE FAMILY MUSTELIDAE: THE MINK (MUSTELA VISON)

1965 ◽  
Vol 43 (1) ◽  
pp. 55-68 ◽  
Author(s):  
A. J. Wood ◽  
I. McT. Cowan ◽  
M. J. Daniel
Keyword(s):  
Body Weight ◽  
Mustela Vison ◽  
Organ Weight ◽  
The Body ◽  
Heart Weight ◽  
Organ Weights ◽  
The Family ◽  
Independent Variable

The relation between certain of the organs and the body weight of ranch raised mink has been examined. The lethal agent used for killing the mink is shown to affect the relative weights of the organs studied. The unsuitability of body weight as an independent variable against which to express organ weights is discussed and it is suggested that heart weight may be a more useful base.

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