Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project.

BACKGROUND: Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. MATERIALS AND METHODS: Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. RESULTS: Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. CONCLUSIONS: Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.

Sexual partner testing for HIV to eliminate mother-to-child HIV transmission: a needs assessment in an urban hospital community clinic.

OBJECTIVE: To characterize pregnant patients' knowledge, attitudes and preferences regarding antenatal HIV testing for themselves and their sexual partners. STUDY DESIGN: Observational, mixed methods study of HIV-negative pregnant women from a university-based urban clinic. Participants completed an anonymous survey about HIV testing for themselves and their partners. Descriptive statistics, bivariable analyses, multivariable logistic regression and qualitative thematic analysis were utilized. RESULTS: One hundred and forty-two patients (mean age 28.6±5.5 years) participated. A majority (57.7%) were married or partnered, and 92.9% reported having at least one current sexual partner. Although a majority (62.8%) reported their partner had a prior HIV test, and 93.0% of these women were aware of test results, only 20.7% reported partner testing had occurred in the past 6 months. Women who had a prior HIV test, who were older or who were non-white were more likely to be aware of their partner's HIV status. A majority (66.9%) of women desired knowledge of their partner's current status and 76.0% believed their partners would like to know his HIV status; in addition, 74% were interested in receiving partner testing at the site of prenatal care. Qualitative analysis demonstrated that health concerns and believing HIV knowledge is important to the relationship were motivators for desiring partner testing. CONCLUSIONS: In this urban community, a majority of pregnant women do not know HIV test results of their sexual partner during the current pregnancy. Women desired to know their partner's HIV status and were receptive to partner testing at the site of prenatal care or other locations. Partner testing may be a critical step toward elimination of seroconversion during pregnancy and maternal-to-child HIV transmission.