Characteristics of post hoc subgroup analyses of oncology clinical trials: A systematic review

BACKGROUND: Subgroup analyses in clinical trials assess intervention effects on specific patient subgroups, ensuring generalizability. However, they are usually only able to generate hypotheses rather than definitive conclusions. This study examined the prevalence and characteristics of post hoc subgroup analysis in oncology. METHODS: We systematically reviewed published subgroup analyses from 2000 to 2022. We included articles presenting secondary, post hoc, or subgroup analyses of interventional clinical trials in oncology, cancer survivorship, or cancer screening, published separately from the original clinical trial publication. We collected cancer type, year of publication, where and how subgroup analyses were reported, and funding. RESULTS: Out of 16 487 screened publications, 1612 studies were included, primarily subgroup analyses of treatment trials for solid tumors (82%). Medical writers contributed to 31% of articles, and 58% of articles reported conflicts of interest. Subgroup analyses increased significantly over time, with 695 published between 2019 and 2022, compared to 384 from 2000 to 2014. Gastrointestinal tumors (25%) and lymphoid lineage tumors (39%) were the most frequently studied solid and hematological malignancies, respectively. Industry funding and reporting of conflicts of interest increased over time. Subgroup analyses often neglected to indicate their secondary nature in the title. Most authors were from high-income countries, most commonly North America (45%). CONCLUSIONS: This study demonstrates the rapidly growing use of post hoc subgroup analysis of oncology clinical trials, revealing that the majority are supported by pharmaceutical companies, and they frequently fail to indicate their secondary nature in the title. Given the known methodological limitations of subgroup analyses, caution is recommended among authors, readers, and reviewers when conducting and interpreting these studies

Genomic Runs of Homozygosity Record Population History and Consanguinity

The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects

Argininosuccinate synthetase activity in cultured human lymphocytes

The activity of argininosuccinate synthetase (E.C. 6.3.4.5), a urea cycle enzyme, was measured in cultured human lymphocytes using a new radioactive assay. Control cells had a maximum specific activity of 15.7±8.7 nmoles per hour per milligram of protein and an apparent K m for citrulline of 2 × 10 −4 m , whereas cells derived from a patient with citrullinemia had no detectable activity. A nutritional variant, selected out of the citrullinemic lymphocyte population by ability to grow in citrulline, had a maximum specific activity of 10.7±3.8 nmoles/hr/mg and an apparent K m for citrulline of 2 × 10 −2 m . These measurements confirm the observation that citrullinemia is associated with a defect in argininosuccinate synthetase activity and provide further evidence that citrullinemia is expressed in cultured lymphocytes. The emergence of a nutritional variant with a partial defect in argininosuccinate synthetase enzyme suggests that this citrullinemic patient has a heterogeneous population of cells, some totally defective and others only partially defective in argininosuccinate synthetase. The new activity assay is described in detail.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44125/1/10528_2004_Article_BF00484469.pd

Citrulline metabolism in normal and citrullinemic human lymphocyte lines

Citrullinemia is one of the five aminoacidurias associated with the Krebs-Henseleit urea cycle. A long-term lymphocyte line (UM-21) derived from a patient with this disease and nine of ten clones of this line were found to have no activity for the enzyme argininosuccinate synthetase (AS), as demonstrated by their inability to grow in medium in which citrulline had been substituted for arginine, by their inability to incorporate arginine-C 14 derived from citrulline-C 14 into cellular protein, and by direct enzyme assay. One clone had normal or nearly normal argininosuccinate synthetase activity, as demonstrated by the same criteria. Nutritional “variants” able to grow logarithmically in medium containing citrulline were isolated from UM-21 and three clones. The apparent K m s of AS for citrulline in UM-21, the ten clones, the variant lines, and a normal line were measured and fell into three groups: AS in UM-21 and nine clones had no measurable apparent K m for citrulline; AS in the variant cells had apparent K m s for citrulline of approximately 20 m m ; and AS in the normal cell line and one clone had apparent K m s for citrulline of 0.2 m m . The data suggest that the defect in the citrullinemic cell lines is due to a mutation in the structural gene coding for argininosuccinate synthetase.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44122/1/10528_2004_Article_BF00485789.pd