We describe a class of nonparametric tests for linkage between a marker and a gene assumed to exist and to govern susceptibility to a disease. The tests are formed by assigning a score to each possible pattern of marker allele sharing (identity-by-descent) among affected pedigree members, and then averaging the scores over all patterns compatible with the observed marker genotype and genealogical relationship of the affected members. Different score functions give different tests. One function, which examines marker allele similarity across pairs of affected pedigree members, gives a test similar to that of Fimmers et al. (1989, in Multipoint Mapping and Linkage Based on Affected Pedigree Members: Genetic Analysis Workshop, R. C. Elston, M. A. Spence, S. E. Hodge, and J. W. MacCluer (eds), 123-128; City: Alan R. Liss). A second function examines allele similarity across arbitrary subsets, not just pairs, of affected members. The resulting test can be more powerful than the one based solely on pairs of affected members. The approach has several advantages: it does not require knowledge of the mode of disease inheritance; it does not require unambiguous determination of identity-by-descent at the marker; it does not suffer from variability due to chance allele similarity among affected members who are unrelated, such as spouses; it allows marker genotypes of unaffected members to contribute information on allele sharing among the affected; it permits calculation of exact P-values. Computational requirements limit the tests to many pedigrees with few (< 16) affected members.

While diffuse large-cell lymphoma (DLCL) is considered to be highly curable with current therapy, treatment failures are observed even with intensive combination chemotherapy regimens. In order to study the prognostic significance of actual dose intensity of chemotherapy in DLCL, we retrospectively analyzed 115 previously untreated patients treated as Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclosphosphamide, vincristine, prednisone, and bleomycin (MACOP-B). The actual relative dose intensity (RDI), the amount of drug actually administered to each patient during the first 12 weeks of therapy, was calculated as standardized to CHOP and analyzed in addition to clinical factors prognostic for survival by univariate analysis. Multivariate recursive partitioning (tree-structured) survival analysis identified the actual RDI of Adriamycin greater than 75% as the single most important predictor of survival. A model incorporating the actual RDI of Adriamycin and performance status, in combination with serum lactate dehydrogenase (LDH) and extranodal disease, defined three overall prognostic groups of patients with respective 3-year survival rates of 89%, 63%, and 18%. The three prognostic groups remained distinct, even when restricted to complete responders. This model was also predictive of survival when dose intensity was analyzed relative to the optimum dose defined for each of the three regimens and when applied to a subgroup of patients aged 50 years or younger. We conclude that actual RDI is an important prognostic factor for survival in DLCL and that analysis of RDI early in the course of treatment may allow modification of the treatment plan.

A subset of patients with HT from low-grade follicular lymphoma to intermediate- or high-grade lymphoma enjoys relatively long-term survival. Patients with limited disease and no previous exposure to chemotherapy have the most favorable prognosis.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 SNPs among a discovery set of 3,523 EOBC incident case and 2,702 population control women aged <=51 years. The SNPs with smallest P-values were examined in a replication set of 3,470 EOBC case and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P-values to obtain a gene-based P-value. We examined the gene with smallest P-value for replication in 1,145 breast cancer case and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P<4×10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P<6×10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P<0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genomewide gene-based threshold of 2.5×10−6. In conclusion, EOBC and LOBC appear to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.