Adherence trajectories in oral therapy for chronic myeloid leukemia: Overview of a research protocol.

Over a quarter of chemotherapy regimens now include oral agents. Individuals living with cancer are now responsible for administering this lifesaving therapy at home by taking every dose as prescribed. One type of oral chemotherapy, tyrosine kinase inhibitors (TKIs), is the current recommended treatment for chronic myeloid leukemia. This targeted therapy has markedly improved survival but comes with significant side effects and financial costs. In the study described in this protocol, the investigators seek to understand the dynamic nature of TKI adherence experienced by individuals diagnosed with CML. Using a mixed-method approach in this prospective observational study, funded by the National Cancer Institute, we seek to describe subjects' adherence trajectories over 1 year. We aim to characterize adherence trajectories in individuals taking TKIs using model-based cluster analysis. Next, we will determine how side effects and financial toxicity influence adherence trajectories. Then we will examine the influence of TKI adherence trajectories on disease outcomes. Additionally, we will explore the experience of patients taking TKIs by interviewing a subset of participants in different adherence trajectories. The projected sample includes 120 individuals taking TKIs who we will assess monthly for 12 months, measuring adherence with an objective measure (Medication Event Monitoring System). Identifying differential trajectories of adherence for TKIs is important for detecting subgroups at the highest risk of nonadherence and will support designing targeted interventions. Results from this study can potentially translate to other oral agents to improve care across different types of cancer.

Characterization and remediation of sample index swaps by non-redundant dual indexing on massively parallel sequencing platforms.

BACKGROUND: Here we present an in-depth characterization of the mechanism of sequencer-induced sample contamination due to the phenomenon of index swapping that impacts Illumina sequencers employing patterned flow cells with Exclusion Amplification (ExAmp) chemistry (HiSeqX, HiSeq4000, and NovaSeq). We also present a remediation method that minimizes the impact of such swaps. RESULTS: Leveraging data collected over a two-year period, we demonstrate the widespread prevalence of index swapping in patterned flow cell data. We calculate mean swap rates across multiple sample preparation methods and sequencer models, demonstrating that different library methods can have vastly different swapping rates and that even non-ExAmp chemistry instruments display trace levels of index swapping. We provide methods for eliminating sample data cross contamination by utilizing non-redundant dual indexing for complete filtering of index swapped reads, and share the sequences for 96 non-combinatorial dual indexes we have validated across various library preparation methods and sequencer models. Finally, using computational methods we provide a greater insight into the mechanism of index swapping. CONCLUSIONS: Index swapping in pooled libraries is a prevalent phenomenon that we observe at a rate of 0.2 to 6% in all sequencing runs on HiSeqX, HiSeq 4000/3000, and NovaSeq. Utilizing non-redundant dual indexing allows for the removal (flagging/filtering) of these swapped reads and eliminates swapping induced sample contamination, which is critical for sensitive applications such as RNA-seq, single cell, blood biopsy using circulating tumor DNA, or clinical sequencing.

Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.

BACKGROUND: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. RESULTS: We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV. CONCLUSIONS: These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease.

Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation.

Copy-number variants (CNVs) have been the predominant focus of genetic studies of structural variation, and chromosomal microarray (CMA) for genome-wide CNV detection is the recommended first-tier genetic diagnostic screen in neurodevelopmental disorders. We compared CNVs observed by CMA to the structural variation detected by whole-genome large-insert sequencing in 259 individuals diagnosed with autism spectrum disorder (ASD) from the Simons Simplex Collection. These analyses revealed a diverse landscape of complex duplications in the human genome. One remarkably common class of complex rearrangement, which we term dupINVdup, involves two closely located duplications ("paired duplications") that flank the breakpoints of an inversion. This complex variant class is cryptic to CMA, but we observed it in 8.1% of all subjects. We also detected other paired-duplication signatures and duplication-mediated complex rearrangements in 15.8% of all ASD subjects. Breakpoint analysis showed that the predominant mechanism of formation of these complex duplication-associated variants was microhomology-mediated repair. On the basis of the striking prevalence of dupINVdups in this cohort, we explored the landscape of all inversion variation among the 235 highest-quality libraries and found abundant complexity among these variants: only 39.3% of inversions were canonical, or simple, inversions without additional rearrangement. Collectively, these findings indicate that dupINVdups, as well as other complex duplication-associated rearrangements, represent relatively common sources of genomic variation that is cryptic to population-based microarray and low-depth whole-genome sequencing. They also suggest that paired-duplication signatures detected by CMA warrant further scrutiny in genetic diagnostic testing given that they might mark complex rearrangements of potential clinical relevance.

Modifiable risk factors for adherence to adjuvant endocrine therapy among breast cancer patients.

OBJECTIVE: Breast cancer incidence and mortality are declining due to improvements in early detection and treatment. One advance in treatment is the development of adjuvant endocrine therapy (AET) for women with hormone receptor positive breast cancer. Despite strong evidence linking AET to better health outcomes, AET adherence continues to be suboptimal. This study tests the hypothesis that patient beliefs about medication mediate the relationship between frequency of physician communication and AET adherence. METHODS: This cross-sectional study utilizes data from patient self-report and medical chart abstraction (N=200). Survey measures included frequency of physician communication, patient beliefs about medicine, AET adherence, and demographic characteristics. RESULTS: Necessity beliefs mediated the relationship between frequency of physician communication and medication adherence (necessity beliefs ß=.18, p<.05; physician communication ß=.13, p>.05). There was no evidence of medication concerns mediating the relationship between frequency of physician communication and medication adherence. CONCLUSION: More frequent physician communication that shapes what patients believe about AET importance may be associated with greater AET adherence; however, frequent physician communication that shapes patient concerns about side effects may not be associated with greater AET adherence. PRACTICE IMPLICATIONS: Research is needed to enhance understanding of the type of physician communication that is most consistently associated with patient beliefs about medication and AET adherence.

Evaluation of the Avon Foundation community education and outreach initiative Community Patient Navigation Program.

INTRODUCTION: Black women in the United States experience disproportionate breast cancer mortality. Culturally appropriate community education on the importance of breast health coupled with the availability of free or low-cost mammography screening services may help improve the use of mammography screening services among Black women. The Avon Foundation Community Patient Navigation Program seeks to fill this need. The current study presents a process and outcome evaluation of this program. METHOD: Trained and uniformed community patient navigators (PNs) host breast health education events where they recruit community members to complete a mammography interest form. Participants are referred to a nurse practitioner who determines eligibility for a free or low-cost mammogram. The community PN delivers telephone follow-up to encourage participants to make and keep their mammogram appointments. RESULTS: Over a 15-month period, 22 community PNs hosted 207 breast health events, which included 9,601 attendees. Three hundred and four participants completed a mammography interest form, and 21% of these individuals received mammograms at the collaborating health facility. Participants who reported breast symptoms were twice as likely to get a mammogram as those who did not report symptoms. DISCUSSION: Community patient navigation may be a useful resource for encouraging mammography screening among underserved women.

A qualitative evaluation of the Avon Foundation Community Education and Outreach Initiative Patient Navigation Program.

This study presents a qualitative evaluation of the Avon Foundation Community Education and Outreach Initiative (CEOI) Patient Navigation Program. Qualitative in-depth interviews were conducted with breast cancer patients (N = 18) of the CEOI Patient Navigation Program. Primary strengths of the program include the nature of the relationship between the patient and navigator, the availability of navigators to attend appointments, and the fact that navigators were breast cancer survivors. The process of enrolling patients into the program was a weakness. Participants described positive experiences with this program. They also identified areas of improvement that are relevant to other patient navigation programs in the US.