Peto Test Research Articles

Oxidative damage in the gastrocnemius predicts long-term survival in patients with peripheral artery disease

Patients with peripheral artery disease (PAD) have increased mortality rates and a myopathy in their affected legs which is characterized by increased oxidative damage, reduced antioxidant enzymatic activity and defective mitochondrial bioenergetics. This study evaluated the hypothesis that increased levels of oxidative damage in gastrocnemius biopsies from patients with PAD predict long-term mortality rates. Oxidative damage was quantified as carbonyl adducts in myofibers of the gastrocnemius of PAD patients. The oxidative stress data were grouped into tertiles and the 5-year, all-cause mortality for each tertile was determined by Kaplan-Meier curves and compared by the Modified Peto test. A Cox-regression model was used to control the effects of clinical characteristics. Results were adjusted for age, sex, race, body mass index, ankle-brachial index, smoking, physical activity, and comorbidities. Of the 240 study participants, 99 died during a mean follow up of 37.8 months. Patients in the highest tertile of oxidative damage demonstrated the highest 5-year mortality rate. The mortality hazard ratios (HR) from the Cox analysis were statistically significant for oxidative damage (lowest vs middle tertile; HR = 6.33; p = 0.0001 and lowest vs highest; HR = 8.37; p < 0.0001). Survival analysis of a contemporaneous population of PAD patients identifies abundance of carbonyl adducts in myofibers of their gastrocnemius as a predictor of mortality rate independently of ankle-brachial index, disease stage and other clinical and myopathy-related covariates.

Lung carcinogenicity by whole body inhalation exposure to Anatase-type Nano-titanium Dioxide in rats.

To investigate the carcinogenicity of anatase-type nano-titanium dioxide (aNTiO2), F344/DuCrlCrlj rats were exposed to aNTiO2 aerosol at concentrations of 0, 0.5, 2, and 8 mg/m3. The rats were divided into 2 groups: carcinogenicity study groups were exposed for two years, and satellite study groups were exposed for one year followed by recovery for 1 day, 26 weeks, and 52 weeks after the end of exposure. In the carcinogenicity groups, bronchiolo-alveolar carcinomas were observed in two 8 mg/m3-exposed males, showing an increasing trend by Peto's test. However, this incidence was at the upper limit of JBRC's historical control data. Bronchiolo-alveolar adenomas were observed in 1, 2, 3, and 4 rats of the 0, 0.5, 2, and 8 mg/m3-exposed females and were not statistically significant. However, the incidence in the 8 mg/m3-exposed females exceeded JBRC's historical control data. Therefore, we conclude there is equivocal evidence for the carcinogenicity of aNTiO2 in rats. No lung tumors were observed in the satellite groups. Particle-induced non-neoplastic lesions (alveolar epithelial hyperplasia and focal fibrosis) were observed in exposed males and females in both the carcinogenicity and satellite groups. Increased lung weight and neutrophils of bronchoalveolar lavage fluid were observed in the 8 mg/m3-exposed carcinogenicity groups. The aNTiO2 deposited in the lungs of the satellite group rats was decreased at 26 weeks after the end of exposure compared to 1 day after the end of exposure. At 52 weeks after the end of exposure, the decreased level was the same at 26 weeks after the end of exposure.

Carcinogenicity and chronic toxicity of butyl methacrylate in rats and mice by a two-year inhalation study.

We conducted a two-year inhalation study of butyl methacrylate using F344/DuCrlCrlj rats and B6D2F1/Crl mice. Rats were exposed to 0, 30, 125 and 500 ppm (v/v) and mice were exposed to 0, 8, 30 and 125 ppm (v/v) using whole-body inhalation chambers. Non-neoplastic lesions developed in the nasal cavities of both rats and mice, but neoplastic lesions were not found. There was also a positive trend in the incidence of large granular lymphocytic (LGL) leukemia in the spleen of male rats. No changes were observed in female rats. Overall, there is some evidence of carcinogenicity in male rats, but there is no evidence of carcinogenicity in female rats. In male mice, there was a positive trend by Peto's test in the incidence of hepatocellular adenomas, and the incidence of hepatocellular adenomas and hepatocellular carcinomas combined was significantly increased compared to the controls by Fisher's exact test in the 30 ppm exposed male group. In female mice, the incidence of hemangiosarcoma in all organs combined showed a positive trend by Peto's test. Therefore, there is some evidence of carcinogenicity in male mice, and there is equivocal evidence of carcinogenicity in female mice.

Association of Sex With Adolescent Soccer Concussion Incidence and Characteristics

Because of the negative consequences of concussion, considerable research efforts have been directed toward understanding the risk factors for sport-related concussion (SRC) and its outcomes to better inform strategies for risk reduction. Girls are suggested to have an increased risk of concussion, warranting exploration into sex-dependent variations in concussion presentation and management, with the potential that this information might inform sex-specific rules directed toward risk reduction within sports. To compare sex-associated differences in epidemiology and concussion management in adolescent soccer players within a prospective, longitudinal high school injury surveillance project. This prospective, longitudinal cohort study assessed male and female soccer athletes from all high schools in the Michigan High School Athletic Association (MHSAA) during academic years 2016-2017 to 2018-2019. Sport-related concussion captured in the MHSAA Head Injury Reporting System. Outcomes included details regarding each documented SRC event, including injury mechanism, immediate management, and return-to-play time. Multiple comparisons were made between male and female athletes regarding SRC risk, mechanism, short-term management, and outcomes. A total of 43 741 male and 39 637 female soccer athletes participated in MHSAA soccer during the 3 consecutive academic years of study (2016-2017: n = 751 schools; 2017-2018: n = 750 schools; and 2018-2019: n = 747 schools). During the 3 years of surveillance, 1507 of the 83 378 soccer athletes (1.8%) were reported to have SRC during soccer participation, including 557 boys (37.0%) and 950 girls (63.0%). Documented SRC risk in female soccer participants was greater than in male soccer participants (risk ratio, 1.88; 95% CI, 1.69-2.09; P < .001). Male soccer athletes most often sustained SRC from contact with another player (48.4%), whereas SRCs in female soccer players recorded in the Head Injury Reporting System were most often from nonplayer contact events (41.9%; P < .001). Adolescent male soccer players with a documented SRC were more likely to be removed from play on the day of injury (odds ratio, 1.54; 95% CI, 1.15-2.06; P = .004). Although the overall median time to return to play was 11 days (interquartile range [IQR], 7-15 days), male athletes typically returned 2 days earlier than female athletes (median, 10 [IQR, 7-14] days vs 12 [IQR, 7-16] days; Peto test P < .001). In this cohort study, sex-associated differences were revealed among adolescent soccer athletes in SRC risk, mechanism of injury, immediate management, and outcomes in injuries documented in a statewide injury reporting system. Thus, consideration might be given to sex-specific approaches to participation and concussion management in the sport.

Clinical Recovery Timelines After Sport-Related Concussion in Men's and Women's Collegiate Sports.

Researchers have identified sex differences in sport-related concussion incidence and recovery time; however, few have examined sex differences in specific recovery trajectories: time to symptom resolution, return to academics, and return to athletic activity across collegiate sports. To examine sex differences in sport-related concussion recovery trajectories across a number of club and varsity sports with different levels of contact. Descriptive epidemiology study. Collegiate varsity and club sports. Sport-related concussions sustained by student-athletes (n = 1974; women = 38.8%) participating in Ivy League sports were monitored between 2013-2014 and 2018-2019. Athletic trainers collected concussive injury and recovery characteristics as part of the Ivy League-Big Ten Epidemiology of Concussion Study's surveillance system. Time to symptom resolution, return to academics, and return to limited and full sport participation were collected. Survival analyses determined the time from injury to each recovery outcome for male and female athletes by sport. Peto tests were used to compare recovery outcomes between men's and women's sports and by sport. The median (interquartile range [IQR]) was 9 days (IQR = 4-18 days) for time to symptom resolution overall, 8 days (IQR = 3-15 days) for return to academics, 12 days (IQR = 8-23 days) for return to limited sport participation, and 16 days (IQR = 10-29 days) for return to full sport participation. We observed differences overall between sexes for median time to symptom resolution (men = 8 days [IQR = 4-17 days], women = 9 days [IQR = 5-20 days]; P = .03) and return to academics (men = 7 days [IQR = 3-14 days], women = 9 days [IQR = 4-17 days]; P < .001) but not for median time to return to athletics (limited sport participation: P = .12, full sport participation: P = .58). Within-sport comparisons showed that women's lacrosse athletes had longer symptom resolution (P = .03) and return to academics (P = .04) compared with men's lacrosse athletes, whereas men's volleyball athletes took longer to return to limited (P = .02) and full (P = .049) sport participation than women's volleyball athletes. Recovery timelines between sexes were different. Athletes in women's sports experienced longer symptom durations and time to return to academics compared with men's sports, but athletes in men's and women's sports presented similar timelines for return to athletics.

Time to Authorized Clearance From Sport-Related Concussion: The Influence of Health Care Provider and Medical Facility.

Return to play after sport-related concussion (SRC) requires authorized clearance from a health care provider (HCP). The variability in HCPs and facilities where athletes seek care may influence return time. To identify the initial examiner, HCPs who authorize clearance to return to play, and medical facilities that authorize clearance to return to play for high school student-athletes after SRC and compare authorized clearance time by HCPs and medical facilities. Prospective cohort study. High school. Student-athletes (n = 16 001) with SRC participating in athletics sponsored by the Michigan High School Athletic Association. Frequencies of initial examiner and authorized clearance for each HCP (doctor of osteopathic medicine, medical doctor, nurse practitioner, physician assistant) and medical facility (neurologist's office; team physician, primary care physician or pediatrician's office [PCP]; hospital; urgent/ready care) for each case of SRC. We calculated Kaplan-Meier curves and Peto tests to evaluate differences in the median time to authorized clearance between HCPs and facilities. Only cases with a date on which clearance to return to play was authorized (80.3%; n = 12 856) were included in the authorized clearance and time-to-return analyses. An athletic trainer was at least 1 of the initial examiners in 71.3% (n = 11 404) of SRC cases; 81.2% (n = 12 990) had only 1 initial examiner. We observed an association between the initial examiner and the medical facility providing clearance for athletic director (χ2 = 52.6, P < .001, V = .06), athletic trainer (χ2 = 172.0, P < .001, V = .12), coach (χ2 = 161.5, P < .001, V = .11), doctor of osteopathic medicine (χ2 = 59.4, P < .001, V = .07), and nurse practitioner (χ2 = 10.0, P = .04, V = .12). Clearance was authorized most frequently by a medical doctor (63.9%, n = 8218) and at a PCP (70.8%, n = 9099). Median (interquartile range) time to authorized clearance varied by facility (urgent/ready care = 7 days [4-11 days], hospital = 9 days [6-14 days], PCP = 10 days [6-14 days], team physician = 12 days [8-16 days], neurologist's office = 13 days [9-20 days]; P < .001). An athletic trainer was the initial examiner more often for males (74.1%) than for females (65.8%). The medical facility where clearance to return to play was authorized also differed between males (PCP = 69.3%, team physician = 11.3%, neurologist's office = 8.4%) and females (PCP = 73.6%, team physician = 8.5%, neurologist's office = 8.3%). Clearance to return to play after SRC was frequently provided by a medical doctor and at a PCP. The median time to return to unrestricted participation after SRC varied by HCP and medical facility. Future researchers should elucidate the reasons for these differences and determine why athletes seek care at different types of medical facilities.

Molecular Predictors for Advanced Papillary Thyroid Carcinoma Recurrence.

Despite its indolent course, one-third of the papillary thyroid carcinoma (PTC) cases relapses, which directly impact on the quality of patients' lives. The molecular predictors of recurrence of PTC are poorly defined. We aimed at evaluating the long-term (10–20 years) prognostic value of aggressiveness markers in advanced PTC. To this end, immunohistochemistry for BRAFV600E, Estrogen receptor α, Progesterone receptor, Ki-67, and E-cadherin were performed in 53 primary advanced PTC from an up to 20 years follow-up patients from a well-characterized Brazilian cohort. Categorical data were summarized using frequencies and groups were compared using Chi-squared and Fisher's exact tests. The expressions of the aggressiveness markers were associated with clinical-pathological data using the single-covariate logistic regression analysis. The Kaplan-Meier method with the Log-rank and Peto tests was used to estimate the probability of PTC-free survival. Persistence and recurrence (active disease) were associated with age (≥55 years), tumor size (>2 cm), extrathyroidal extension, local aggressiveness, macroscopic lymph node metastasis, and TNM stage at initial treatment. The BRAFV600E mutation status was associated with extrathyroidal extension, local aggressiveness, and inversely associated with distant metastasis at initial treatment. All progesterone receptor-positive patients had active disease and displayed a shorter time of PTC-free survival than the negative ones using the Kaplan-Meir analysis (p = 0.001, Log Rank; p = 0.005, Peto). Loss of E-cadherin expression was associated with an increase in the probability of active disease (OR = 3.75). BRAFV600E could be useful as a biomarker of local aggressiveness, while PR positive and E-cadherin loss of expression could predict the recurrence of advanced PTC.

Exact Statistical Tests on Comparing Tumor Incidence Trend in Transgenic Mouse Carcinogenicity Studies

ABSTRACTStatistical positive trend tests to predict drugs' tumorigenic potential for long-term carcinogenicity studies, for example, Peto's test, are well accepted in practice and by regulatory agencies. Recently, short-term transgenic mouse studies become widely used as an alternative to lifetime mouse carcinogenicity studies. In general, the tumor incidence rates in a short-term study are much lower than those for a traditional long-term study, so exact positive trend test should be used. However, little is discussed about exact statistical trend tests for transgenic mouse studies. In this article, we evaluated three types of exact methods for testing tumor trend via simulation: exact Cochran-Armitage (C-A) test, exact Peto's test, and a proposed conditional exact Poly-k test. We show, via a simulations study, that the Type I error rate and statistical power are very similar for these three exact tests under various mortality rates and tumorigenic patterns. Overall, we recommend using exact C-A test to compare tumor incidence trend for short-term transgenic mouse studies. When survival adjustment is needed, the proposed conditional exact Poly-k test can be used as an alternative.

Exact Poly-K Test

For animal carcinogenicity study with multiple dose groups, positive trend test and pairwise comparisons of treated groups with control are generally performed using the Cochran-Armitage, Peto test, or Poly-K test. These tests are asymptotically normal. The exact version of Cochran-Armitage and Peto tests are available based on the permutation test assuming fixed column and row totals. For Poly-K test column totals depend on the mortality pattern of the animals and can not be kept fixed over the permutations of the animals. In this work a modification of the permutation test is suggested that can be applied on exact Poly-K test.

Testing the treatment effect on competing causes of death in oncology clinical trials.

BackgroundChemotherapy is expected to reduce cancer deaths (CD), while possibly being harmful in terms of non-cancer deaths (NCD) because of toxicity. Peto’s log-rank test is popular in the medical literature, but its operating characteristics are barely known. We compared this test to the most common ones in the statistical literature: the cause-specific hazard test and Gray’s test on the hazard of the subdistribution. We investigated for the first time the impact of reclassifications of causes of death (CoD) after recurrences, and of misclassification of CoD.MethodsWe present a simulation study in which we varied the censoring rate and the correlation between CD and NCD times, we generated recurrence times to study the role of the reclassification of CoD, and we added 20% misclassified CoD. We considered four scenarios for the treatment effect: none; none for CD and negative for NCD; positive for CD and none for NCD; positive for CD and negative for NCD. We applied the three tests to a randomized clinical trial evaluating adjuvant chemotherapy in 1,867 patients with non-small-cell lung cancer.ResultsMost often the three tests well preserved their nominal size, Gray’s test did not when the treatment had an effect on the competing CoD. With a high rate of misclassified CoD, Gray’s and the cause-specific tests lost much of their power, whereas the Peto’s test had the highest power. The cause-specific test had inflated size for NCD when the treatment was beneficial for CD with many misclassified CoD, but had the highest power for NCD when the treatment had no effect on CD, and had similar power to Peto’s test for CD when the treatment had no effect on NCD. Gray’s test performed best when the effect on the two CoD was opposite. The higher the censoring, the lower the rejection probabilities of all the tests and the smaller their differences.ConclusionsIn this first head-to-head comparison of the three tests, the cause-specific test often proved to be the most reliable. Comparing results with and without misclassification of the CoD, Peto’s test was the least influenced by the presence of such misclassification.

Analysis of graded lesions in long-term carcinogenicity studies

Analysis of graded lesions in long-term carcinogenicity studies John S Fry, Peter N Lee, Jan S HamlingPN Lee Statistics and Computing, Sutton, UKAbstract: In long-term carcinogenicity studies, the Peto test is the standard method for analyzing lesions that are not observable in life, taking into account differential between-group mortality. This method requires knowledge for each animal in each group of when the animal died, whether a lesion was seen postmortem, and the context of observation (ie, whether the lesion was fatal [considered to have contributed to its death] or whether it was incidental [seen in an animal dying for an unrelated reason]). The Peto test was not designed to take severity of the lesion into account. Age-adjusted analysis taking severity into account can be carried out using a stratified version of the Kruskal&ndash;Wallis one-way analysis of variance by ranks, but this does not take context of observation into account. Here, we describe an extended version of the stratified Kruskal&ndash;Wallis test that both allows analysis of lesions graded on severity and takes fatality of the lesion into account. This includes both a test for between-group heterogeneity and a test for dose-related trend, and provides a powerful method for analyzing such data. The Peto and Kruskal&ndash;Wallis tests may be considered special cases of this more general test. The test may be applied not only to nonneoplastic lesions (such as chronic progressive nephropathy), where pathologists often grade severity on a 5-point scale, but also to preneoplastic and neoplastic lesions, carrying out a single analysis of focal hyperplasia, benign tumor, and malignant tumor of a specific histological type, regarding these as successive stages of a progressive condition.Keywords: carcinogenicity tests, survival analysis, heterogeneity, trend, stratified analysis

Should We Assess Tumorigenicity With the Peto or Poly-k Test?

The IARC guidance document on testing for tumorigenicity in long-term animal experiments (Peto et al. 1980) recommended a statistical test for dose-related trend that stratifies animals dying with tumors of a specific type according to whether the tumor was observed because it killed the animal (fatal context) or because of a competing cause of death (incidental context). The test has become known as Peto’s cause-of-death (COD) test or, simply, the Peto test, in recognition of Richard Peto’s lead authorship of the 1980 IARC document. In 1988 John Bailer and Chris Portier developed the Poly-k test for tumorigenicity which does not require a COD determination (Bailer and Portier 1988). Instead it relies on the assumption that the distribution of time to tumor onset can be expressed as a function of the kth power of time. Animals dying without tumors during the course of an experiment contribute to the test statistic according to weights determined by this kth power. Bailer and Portier recommended using k=3 based on an empirical study of historical bioassay data. This article presents construction and characteristics of the Peto and Poly-k tests, a limited comparison of size and power, a view of their regulatory standing, and some modifications.

Sepsis is a major determinant of outcome in critically ill HIV/AIDS patients

IntroductionNew challenges have arisen for the management of critically ill HIV/AIDS patients. Severe sepsis has emerged as a common cause of intensive care unit (ICU) admission for those living with HIV/AIDS. Contrastingly, HIV/AIDS patients have been systematically excluded from sepsis studies, limiting the understanding of the impact of sepsis in this population. We prospectively followed up critically ill HIV/AIDS patients to evaluate the main risk factors for hospital mortality and the impact of severe sepsis on the short- and long-term survival.MethodsAll consecutive HIV-infected patients admitted to the ICU of an infectious diseases research center, from June 2006 to May 2008, were included. Severity of illness, time since AIDS diagnosis, CD4 cell count, antiretroviral treatment, incidence of severe sepsis, and organ dysfunctions were registered. The 28-day, hospital, and 6-month outcomes were obtained for all patients. Cox proportional hazards regression analysis measured the effect of potential factors on 28-day and 6-month mortality.ResultsDuring the 2-year study period, 88 HIV/AIDS critically ill patients were admitted to the ICU. Seventy percent of patients had opportunist infections, median CD4 count was 75 cells/mm3, and 45% were receiving antiretroviral therapy. Location on a ward before ICU admission, cardiovascular and respiratory dysfunctions on the first day after admission, and the presence of severe sepsis/septic shock were associated with reduced 28-day and 6-month survival on a univariate analysis. After a multivariate analysis, severe sepsis determined the highest hazard ratio (HR) for 28-day (adjusted HR, 3.13; 95% CI, 1.21-8.07) and 6-month (adjusted HR, 3.35; 95% CI, 1.42-7.86) mortality. Severe sepsis occurred in 44 (50%) patients, mainly because of lower respiratory tract infections. The survival of septic and nonseptic patients was significantly different at 28-day and 6-month follow-up times (log-rank and Peto test, P < 0.001).ConclusionsSevere sepsis has emerged as a major cause of admission and mortality for hospitalized HIV/AIDS patients, significantly affecting short- and longer-term survival of critically ill HIV/AIDS patients.

Seedling biomass allocation and vital rates of cloud forest tree species: Responses to light in shade house conditions

Patterns of above- and below-ground biomass allocation in seedlings of nine common cloud forest (CF) tree species of western Mexico were examined under varying controlled light conditions using artificial shade houses. We analysed the relationships between vital rates (growth and survival) and four morphological traits (SLA, biomass allocation to stems, leaves and roots). We hypothesised that these traits represent differentiation axes in the way seedlings face the heterogeneous light regime typical of the CF understorey. For all species, traits between the different light levels, i.e. allocation to leaves, roots and stems differed among light levels. Five species had the largest SLA in the lowest light levels at the end of the experiment ( Citharexylum, Dendropanax, Fraxinus, Quercus and Magnolia). Juglans was the only species with a large SLA at the highest light level (377.47 cm 2 g −1). In contrast, light levels did not cause any significant variation in SLA of Persea and Simplococarpon at the end of the experiment. The relative height growth rates (RHGR) of the seedlings of five species were significantly different between light levels ( P < 0.05). Overall, all species grew better in the highest light levels. The RHGR of three species were correlated positively with SLA. In turn, allocation to stem, leaves and root biomass were strongly correlated with the RHGR of five species (e.g. Citharexylum, Dendropanax and Fraxinus). Survival did not vary significantly between treatments in any species, only in the case of Simplococarpon ( P < 0.05) and was correlated with all morphological variables. For this species, Peto and Peto's test showed a significantly larger survival of seedlings in the highest light level. The mean responses of these species based on all traits to the controlled light variation did not differed significantly. Our results show that these species display a wide range of resource allocation patterns when exposed to the varying light conditions that may be found in the forest understorey and highlight the role of morphological traits in this variation.

Limbal Stem Cells Transplantation in the Reconstruction of the Ocular Surface: 6 Years Experience

To analyze the graft survival rate and stability of the corneal surface in patients who underwent limbal stem cell transplantation. Three surgical techniques were performed based on the origin of the ocular surface lesion: conjunctival limbal autograft (CLAU), living-related conjunctival limbal autograft (lr-CLAL), and keratolimbal allograft (KLAL) transplantations. Nonrandomized consecutive comparative case series study. Eighty-four patients (90 eyes; 31 women and 53 men; age range: 11-78 years) were included in the study. Mean follow-up was 31.2 months (range: 6-72 months). Patients were divided into three groups: CLAU, lr-CLAL, and KLAL, comprising 21, 26, and 43 eyes, respectively. Graft survival rate and clinical success of the stem cell transplantation was confirmed by impression cytology. The Kaplan Meier survival curve and generalized Peto tests were used for the analyses. Graft survival rate and the regularity of the corneal surface differed significantly between the allo- and autografts. The 3-year and 6-year graft survival rates were 76.1% and 61.9%, respectively, for the autologous transplantation group, and 59.4% and 46.3%, respectively, for the allogeneic transplantation group. Corneal surface restoration correlated with positive staining for corneal epithelial cells in impression cytology. Significantly better long-term outcomes were achieved with autotransplantation of the limbus compared with allogeneic limbal grafts from living-related and cadaveric donors.

A Comparison of False Positive Rates of Peto and Poly-3 Methods for Long-Term Carcinogenicity Data Analysis Using Multiple Comparison Adjustment Method Suggested by Lin and Rahman

Statistical analyses of two-year carcinogenicity data include tests for dose-response relationship (positive trend) among the increasing doses and pairwise comparisons of treated groups with control in tumor incidence by organ/tumor combination. There are two major concerns in analyzing carcinogenicity data, namely, adjustment for the difference in mortality due to drug toxicity and adjustment for the multiplicity due to multiple testing of trends and pairwise differences by organ tumor combination. A widely used method for testing dose-response relationship is the method suggested by Peto et al. (Peto test). The Peto test adjusts the mortality differences among treatment groups by partitioning the entire study period into several intervals, analyzing the data separately for each interval, and then combining them using the Mantel-Haenszel procedure. The denominator for the calculation of the proportion of tumor bearing animals is determined from the cause of death information tumor data. In later works, researchers have expressed concerns regarding the construction of suitable intervals for mortality adjustment. Also according to the opinion of many pathologists it is difficult to accurately specify retrospectively if a tumor is the real cause of death of an animal. This information may be imprecise. Hence, many times results of analysis using the Peto test are questioned due to the inaccurate cause of death information. An alternative to the Peto test was suggested by Bailer and Portier, popularly known as Poly-K test. Unlike the Peto test, this test does not need any arbitrary partitioning of the study period or the cause of death information. This test for trend in tumor incidence adjusts the differences in mortality among treatment groups by assigning a weight of less than one to an animal that died early without developing the tumor; and a weight of one to an animal that died with the tumor or survived to the end of the study. The sum of the assigned weights of animals in a treatment group is then used as the denominator for the calculation of proportion of tumor-bearing animals for the group. The less-than-one weight assigned to an animal is the fraction of the animal's surviving time in the study over the maximum time of the study with a power k. The power k of the fraction is determined by the distribution of tumor onset times of the tumor. The Poly-K test may have some advantages over the Peto test in the sense that it does not require the cause of death information, which is an essential part for the Peto test. However, the performance of the Poly-K test in controlling the false positive rate in comparison to the Peto test is unknown and of great interest in the regulatory environment. In this work the authors compared the overall false positive rates of the Peto and Poly-K tests using the Lin-Rahman multiple comparison adjustment based on some simulation results.

A Two-Stage Procedure for Comparing Hazard Rate Functions

SummaryComparison of two hazard rates is important in applications that are related to times to occurrence of a specific event. Conventional comparison procedures, such as the log-rank, Gehan–Wilcoxon and Peto–Peto tests, are powerful only when the two hazard rates do not cross each other. Because crossing hazard rates are common in practice, several procedures have been proposed in the literature for comparing such rates. However, most of these procedures consider only the alternative hypothesis with crossing hazard rates; many other realistic cases, including those when the two hazard rates run parallel to each other, are excluded from consideration. We propose a two-stage procedure that considers all possible alternatives, including ones with crossing or running parallel hazard rates. To define its significance level and p-value properly, a new procedure for handling the crossing hazard rates problem is suggested, which has the property that its test statistic is asymptotically independent of the test statistic of the log-rank test. We show that the two-stage procedure, with the log-rank test and the suggested procedure for handling the crossing hazard rates problem used in its two stages, performs well in applications in comparing two hazard rates.

A weight-adjusted Peto?s test when cause of death is not assigned

A new statistical testing approach using a weighted logrank statistic is developed for rodent tumorigenicity assays that have a single terminal sacrifice but not cause-of-death data. Instead of using cause-of-death assignment by pathologists, the number of fatal tumors is estimated by a constrained nonparametric maximum likelihood estimation method. For data lacking cause-of-death information, the Peto test is modified with estimated numbers of fatal tumors and a Fleming–Harrington-type weight, which is based on an estimated tumor survival function. A bootstrap resampling method is used to estimate the weight function. The proposed testing method with the weight adjustment appears to improve the performance in various situations of single-sacrifice animal experiments. A Monte Carlo simulation study for the proposed test is conducted to assess size and power of the test. This testing approach is illustrated using a real data set.

Extension of Peto's Test by Attribution of Tumor Lethality in the Absence of Cause‐of‐Death Information

AbstractA new statistical testing approach is developed for rodent tumorigenicity assays that have a single terminal sacrifice or occasionally interim sacrifices but not cause‐of‐death data. For experiments that lack cause‐of‐death data, statistically imputed numbers of fatal tumors and incidental tumors are used to modify Peto's cause‐of‐death test which is usually implemented using pathologist‐assigned cause‐of‐death information. The numbers of fatal tumors are estimated using a constrained nonparametric maximum likelihood estimation method. A new Newton‐based approach under inequality constraints is proposed for finding the global maximum likelihood estimates. In this study, the proposed method is concentrated on data with a single sacrifice experiment without implementing further assumptions. The new testing approach may be more reliable than Peto's test because of the potential for a misclassification of cause‐of‐death by pathologists. A Monte Carlo simulation study for the proposed test is conducted to assess size and power of the test. Asymptotic normality for the statistic of the proposed test is also investigated. The proposed testing approach is illustrated using a real data set.

The Society of Toxicologic Pathology's recommendations on statistical analysis of rodent carcinogenicity studies.

TheSociety forToxicologicPathology(STP)isanonproe t organization dedicated to improving the discipline of toxicologic pathology through education and professional interactions. The Society’s membership includes over 800 pathologists and toxicologists involvedworldwide in the nonclinical assessment of toxicity and carcinogenicity of chemicals, pharmaceutical candidates, and medical devices. Many of the study pathologists who interpret rodent carcinogenicity studies are members of the STP. The STP, in conjunction with representatives of the U.S. Food and Drug Administration, recognized that there were issues in the application of statistical methodstocarcinogenicitystudies (2).While most pharmaceutical companies used the Peto test (5), some did not categorize neoplasms as Fatal or Incidental (no contexts ofobservationswereassigned).Somecategorizedneoplasms as Fatal or Incidental based solely on the type of neoplasm (diagnostic terminology) rather thanon an animal-by-animal basis. Others categorized neoplasms as Fatal or Incidental based on the gross and microscopic e ndings for each animal. There were no guidelines for consistent assignment of Fatal and Incidental categories. The STP created an ad hoc Peto Working Group to review statistical methods for rodent carcinogenicity studies and make recommendations on how microscopic observations from these studies could be consistently and reliably categorized for analysis using existing statistical methods. The STP Peto Working Group has reviewed the FDA draftGuidanceforIndustry‐StatisticalAspectsoftheDesign, Analysis, and Interpretation of Chronic Rodent Carcinogenicity Studies of Pharmaceuticals (4) and has provided written comments and suggestions to FDA regarding this draft guidance. At the time these comments were provided, the STP was still gathering information and evaluating the use of pathology data in statistical analysis of rodent carcinogenicity studies. The STP has since solicited and published explanations and recommendations of best statistical practices from biostatisticians familiar with rodent carcinogenicity studies, and some positions provided by the STP to the FDA have been modie ed. The Peto Working Group also sponsored a discussion of the Peto test and the Poly-3 test with the STP membership duringthe 2001 STP annual meeting.Theopinionsofabroadsegmentofpathologistsinvolved with rodent carcinogenicity studies varied and included: 1. Many pathologists believe that experienced pathologists can accurately and reliably determine if a neoplasm contributed to death or euthanasia of an individual animal, based on a review of clinical, necropsy, and microscopic e ndings for that individual. While most pathologists are