Cecilia A. Cotton

Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the national Wilms tumor study group

We evaluated the use of alternating cycles of cyclophosphamide/etoposide and carboplatin/etoposide in children entered on National Wilms Tumor Study (NWTS)‐5 who were diagnosed between August 1, 1995 and May 31, 2002 and who relapsed after chemotherapy with vincristine, actinomycin D, and doxorubicin (VAD) and radiation therapy (DD‐4A).

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: A report from the National Wilms Tumor Study Group

NWTS‐5 was a multi‐institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed.

Early and Late Mortality After Diagnosis of Wilms Tumor

PURPOSE To assess rates and causes of mortality in patients with Wilms tumor (WT). METHODS Through 2002, 6,185 patients enrolled onto the National Wilms Tumor Study between 1969 and 1995 were actively observed. Deaths were classified on the basis of medical records as the result of original disease, late effects (including second malignant neoplasms [SMNs], cardiac causes, pulmonary disease, and renal failure), or other causes. Standardized mortality ratios (SMRs) and Cox regression were used to assess the effects of sex, age, and calendar period of diagnosis on mortality. RESULTS Within 5 years of WT diagnosis, 819 deaths occurred, and 159 deaths occurred among 4,972 known 5-year survivors. The SMR was 24.3 (95% CI, 22.6 to 26.0) for the first 5 years, was 12.6 (95% CI, 10.0 to 15.7) for the next 5 years, and remained greater than 3.0 thereafter. For deaths in the first 5 years, the mortality risk decreased by 5-year calendar period of diagnosis (rate ratio [RR] = 0.78 per period). No such trend occurred for later deaths. Among 5-year survivors, 62 deaths were attributed to late effects of treatment or disease, including 27 to SMNs. A trend of decreased risk with calendar period of diagnosis was observed for late-effects mortality (RR = 0.86; 95% CI, 0.67 to 1.10) and for SMN mortality (RR = 0.82; 95% CI, 0.55 to 1.21). CONCLUSION Although the survival outlook for WT patients has improved greatly over time, survivors remain at elevated risk for death many years after their original diagnosis.

Synchronous bilateral Wilm's tumor with complete radiographic response managed without surgical resection: a report from the National Wilm's Tumor Study 4

PURPOSE We reviewed the long-term local tumor control in patients with bilateral Wilms tumor (BWT) who received no definitive surgical therapy to one kidney after complete radiographic resolution after initial chemotherapy. METHODS National Wilms Tumor Study 4 (NWTS-4) enrolled 3335 patients (pts) during the period August 1986 to August 1994. There were 188 pts with BWT or 5.6% of the total enrolled. The treatment records and imaging reports were reviewed to ascertain those children who had documented tumors without definitive surgical therapy after initial treatment. Patients who did not have renal surgery because of progression of tumor were excluded from this study. RESULTS Eleven children had no definitive surgical treatment of renal lesions in one kidney (right, 6; left, 5) after initial treatment with chemotherapy and/or radiation therapy. The pretreatment size of the lesions were less than 3 cm (4 pts), 3 to 6 cm (5 pts), more than 6 cm (1 pt), and unknown (1 pt). Prechemotherapy biopsy was performed in 6 of 11 patients. Lesions were less than 3 cm (1 pt), 3 to 6 cm (3 pts), more than 6 cm (1 pt), and unknown (1 pt). Four biopsy specimens showed favorable Wilms histologic findings. One lesion (4 cm) showed an intralobar nephrogenic rest, another lesion of unknown size was read as favorable histologic findings vs perilobar nephrogenic rest. Biopsy was not performed on 5 lesions (4 pts, <1 cm; 1 pt, 3cm). Only 2 children in this study received radiation treatment. One child received 1050 cGy whole abdominal radiation, and 1 child received 1060 cGy to the left flank postnephrectomy. Radiation therapy was not given to any patient because of failure of the tumor to respond to chemotherapy. Five patients received treatment regimen EE-4A, dactinomycin, and vincristine. The duration of therapy ranged from 24 to 102 weeks for an average of 55.6 weeks. Three patients received treatment regimen DD-4A, dactinomycin, vincristine, and doxorubicin for 28, 52, and 52 weeks, respectively. Three patients received 2 separate regimens of chemotherapy. One child was treated with dactinomycin, vincristine, and cyclophosphamide for 60 weeks and then received regimen EE-4A for 24 weeks. Another patient received regimen EE-4A for 16 weeks and then regimen DD4-A for 36 weeks. One child received regimen EE-4-A for 12 weeks and then regimen DD4A for 40 weeks. Management of the contralateral kidney was complete nephrectomy in all 11 patients. There were no local relapses in the renal tumor bed. All patients were alive at a median follow-up of 9 years (range, 9 months to 15 years). CONCLUSION Children with synchronous BWT or Wilms tumor and contralateral nephrogenic rests that have radiographic resolution, after initial treatment, have a low risk for local relapse. These children should be followed by serial imaging.

Causal inference in nonrandomized studies via propensity score methods

I n randomized trials, random assignment of treatment to patients ensures balance across study arms with respect to observed and unobserved risk factors. Direct comparisons between groups can therefore be made and any difference seen can be attributed to the causal effect of treatment. When treatment is assigned by methods other than random allocation, direct comparisons between treatment groups will typically yield biased estimates of the causal effect of treatment. This bias arises due to systematic differences in the distribution of risk factors between groups. For example, if older patients are less likely to be given a particular treatment and more likely to experience a good outcome, a direct comparison would be biased in favor of the treatment. This is referred to as treatment selection bias. Propensity scores play a central role in an increasingly popular method of adjusting for treatment selection bias on observational studies. Suppose we have a collection of patients, some of who received a treatment of interest and some of who received a reference treatment we refer to as the standard of care. Suppose an outcome of interest for each patient as well as a number of baseline characteristics was recorded. To obtain a valid estimate of the causal effect of treatment we compare a group of treated patients with a group of patients who received the standard of care, but were otherwise similar with respect to all baseline characteristics. Below we describe how propensity score methods can be used for analysis in such settings, provide a simple worked example, and consider the advantages and limitations of these methods. DEFINITON OF A PROPENSITY SCORE

Sex- and age-of-onset-based locus heterogeneity in asthma.

Asthma is a complex disease with a genetic component. The results of genome‐wide linkage studies imply that locus heterogeneity is likely to be an important feature of the genetics of asthma. To attempt to reduce locus heterogeneity, we hypothesized that the following may form the bases for locus heterogeneity at some asthma susceptibility loci: sex of affected individuals, parental origin of alleles shared by affected sib pairs, and age of onset of wheeze. Analysis of such strata may assist in the identification of novel susceptibility loci, or reveal the basis for locus heterogeneity at previously identified loci. Genotype and phenotype data from genome‐wide linkage searches for asthma susceptibility loci from three populations were analyzed. Some regions demonstrated evidence for linkage to affected individuals of a particular sex. There was evidence for excess maternal allele sharing at regions on chromosomes 9 and 11. Regions on chromosomes 2 and 6 were linked to late and early age at onset of wheeze in asthma, respectively. These analyses suggest that the bases that we selected for stratification may be appropriate at certain susceptibility loci for asthma, and may therefore assist in the fine mapping of such loci. Differences in such variables between studies may explain apparent nonreplication of linkage results.

Mortality ascertainment of participants in the National Wilms Tumor Study using the National Death Index: comparison of active and passive follow-up results

Long term studies of childhood cancer survivors are hampered by difficulties in tracking young adult participants. After performing a National Death Index (NDI) search we sought to identify which factors best predicted a match among known decedents from the National Wilms Tumor Study (NWTS) and to determine if record linkage could substitute for missing follow-up in a cohort of NWTS survivors. To our knowledge, this is the first study to compare passive mortality follow-up using the NDI to active follow-up of a childhood and young adult population. Records for 984 known decedents and 3,406 subjects whose January 1, 2002 vital status was unknown were sent to the NDI in June 2003. In April 2005 NWTS follow-up records were used to reassess January 1, 2002 vital status. Matches were established for 709 of 789 known decedents (sensitivity 89.9%) with a date of death between 1979 and 2001, the calendar period covered by the NDI at the time of the search. No matches were identified among 1,052 subjects known to be alive in 2002 (specificity 100%). Factors associated with decreased sensitivity were an unknown social security number (sensitivity 87.8%), Hispanic ethnicity (76.4%) and foreign birth (56.5%). For 2,351 subjects with 2002 vital status unknown who had 13,166 pre 2002 person-years of missing observation, only 18 deaths were ascertained by the NDI whereas 79.3 were expected based on NWTS mortality data. Mortality analyses based strictly on NDI search results and those based on NWTS follow-up augmented with NDI search results yielded inflated estimates of the 15 year survival rate when compared with estimates based on NWTS active follow-up. Match rates were comparable to those observed in adult populations. Since the same selection factors were likely associated with NDI failure to match and NWTS loss to follow-up, use of the NDI to fill in missing follow-up data appears unwarranted.

Development of a decision tree to classify the most accurate tissue-specific tissue to plasma partition coefficient algorithm for a given compound

Physiologically based pharmacokinetic (PBPK) modeling is a tool used in drug discovery and human health risk assessment. PBPK models are mathematical representations of the anatomy, physiology and biochemistry of an organism and are used to predict a drug’s pharmacokinetics in various situations. Tissue to plasma partition coefficients (Kp), key PBPK model parameters, define the steady-state concentration differential between tissue and plasma and are used to predict the volume of distribution. The experimental determination of these parameters once limited the development of PBPK models; however, in silico prediction methods were introduced to overcome this issue. The developed algorithms vary in input parameters and prediction accuracy, and none are considered standard, warranting further research. In this study, a novel decision-tree-based Kp prediction method was developed using six previously published algorithms. The aim of the developed classifier was to identify the most accurate tissue-specific Kp prediction algorithm for a new drug. A dataset consisting of 122 drugs was used to train the classifier and identify the most accurate Kp prediction algorithm for a certain physicochemical space. Three versions of tissue-specific classifiers were developed and were dependent on the necessary inputs. The use of the classifier resulted in a better prediction accuracy than that of any single Kp prediction algorithm for all tissues, the current mode of use in PBPK model building. Because built-in estimation equations for those input parameters are not necessarily available, this Kp prediction tool will provide Kp prediction when only limited input parameters are available. The presented innovative method will improve tissue distribution prediction accuracy, thus enhancing the confidence in PBPK modeling outputs.

Confidence intervals for candidate gene effects and environmental factors in population-based association studies of families

Complex diseases are influenced by both genetic and environmental factors. Studies of individuals or of families can be used to examine the association of genetic factors, such as candidate genes, and other risk factors with the presence or absence of complex disorders. If families are investigated, whether or not they are randomly ascertained, possible familial correlation among observations must be considered. We have compared two statistical approaches for analyzing correlated binary data from randomly ascertained nuclear families. The generalized estimating equations approach (GEE) can be used to adjust for familial correlation. The relationship between covariates and the response is modelled, and the correlations among family members are treated as nuisance parameters. For comparison, we have proposed two strategies from a hierarchical nonparametric bootstrap approach. One strategy (S1) samples family units, preserving the structure and correlation within each family. A second and novel strategy (S2) also samples family units but then randomly samples offspring with replacement in each family. We applied the methods to data from a study of cardiovascular disease, and followed up with a simulation study in which family data were generated from an underlying multifactorial genetic model. Although the bootstrap approach was more computationally demanding, it outperformed the GEE in terms of confidence interval coverage probabilities for all sample sizes considered.

Estimation of parametric failure time distributions based on interval‐censored data with irregular dependent follow‐up

Event history studies based on disease clinic data often face several complications. Specifically, patients may visit the clinic irregularly, and the intermittent observation times could depend on disease-related variables; this can cause a failure time outcome to be dependently interval-censored. We propose a weighted estimating function approach so that dependently interval-censored failure times can be analysed consistently. A so-called inverse-intensity-of-visit weight is employed to adjust for the informative inspection times. Left truncation of failure times can also be easily handled. Additionally, in observational studies, treatment assignments are typically non-randomized and may depend on disease-related variables. An inverse-probability-of-treatment weight is applied to estimating functions to further adjust for measured confounders. Simulation studies are conducted to examine the finite sample performances of the proposed estimators. Finally, the Toronto Psoriatic Arthritis Cohort Study is used for illustration. Copyright