Conducting Molecular Epidemiological Research in the Age of HIPAA: A Multi-Institutional Case-Control Study of Breast Cancer in African-American and European-American Women

Breast cancer in African-American (AA) women occurs at an earlier age than in European-American (EA) women and is more likely to have aggressive features associated with poorer prognosis, such as high-grade and negative estrogen receptor (ER) status. The mechanisms underlying these differences are unknown. To address this, we conducted a case-control study to evaluate risk factors for high-grade ER- disease in both AA and EA women. With the onset of the Health Insurance Portability and Accountability Act of 1996, creative measures were needed to adapt case ascertainment and contact procedures to this new environment of patient privacy. In this paper, we report on our approach to establishing a multicenter study of breast cancer in New York and New Jersey, provide preliminary distributions of demographic and pathologic characteristics among case and control participants by race, and contrast participation rates by approaches to case ascertainment, with discussion of strengths and weaknesses

Germline and somatic variation in melanoma: Epidermal growth factor, microsatellite instability, and population variation in nevi density.

Variation in melanoma susceptibility varies widely among Caucasian populations. This dissertation evaluated germline and somatic variation in melanoma and geographic heterogeneity in nevi density in populations of European ancestry. We investigated a single nucleotide polymorphism in the epidermal growth factor (EGF) gene that had been previously described as a risk factor for melanoma. We conducted case-control analyses using participants collected as part of the Genes, Environment and Melanoma Study, a large, international case-control study of melanoma using two different study designs including a classic comparison of incident cases to unaffected controls and a novel design comparing multiple primary melanoma cases to those with single primary melanoma. The two analytic approaches used in this study provide evidence against a strong association between EGF 61*G and susceptibility to incident primary melanoma. In a second study, we combined molecular tools and epidemiologic techniques to evaluate independent histologic and phenotypic predictors of microsatellite instability in primary melanoma. We found that the MSI-High phenotype is rare in melanoma, and that the MSI-Low phenotype is observed in a subset (36%) of primary melanoma. Furthermore, histologic characteristics and phenotypic factors did not differ with respect to the presence of either low or high levels of microsatellite instability in primary melanoma. Although, high level instability was significantly associated with tumor location. Because there are geographic gradients in the density of benign nevi that serve as markers of melanoma risk, this dissertation also investigated geographic and population variation in nevi density among European populations. In multivariable analysis, study center, ancestral origin and degree of freckling were independent predictors of nevi density. Genetic cluster analysis was unable to differentiate European subpopulations in simulations representative of the underlying allele frequencies in the study sample. Thus, self-defined ancestral labels may provide more useful information regarding environmental and phenotypic risk factors for benign nevi and melanoma than genetic cluster analysis, suggesting that strategies to account for population stratification may not require extensive genotyping. Further work is required to characterize germline and somatic variation in melanoma, and the relevance of heterogeneity observed in nevi density among European populations.Ph.D.Health and Environmental SciencesOncologyPublic healthUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124610/2/3150145.pd

Safety of 4-valent human papillomavirus vaccine in males: a large observational post-marketing study

The 4-valent human papillomavirus (HPV) vaccine (4vHPV vaccine), Gardasil®, is indicated for the prevention of several HPV-related diseases. The objective was to assess the safety of 4vHPV vaccine administered to males as part of routine care. The study used a US health insurance claims database, and included males, age 9 to 26 years, who initiated 4vHPV between October 2009 and December 2016. General safety outcomes were identified using ICD diagnosis codes associated with emergency room visits and hospitalizations in the claims database in risk periods (Days 1–60 and Days 1–14 following vaccine administration) and self-comparison periods (Days 91–150 and 91–104 for the Days 1–60 and Days 1–14 analysis, respectively). Incidence rates (IRs) and relative rates (RRs) with 95% confidence intervals (CIs) were calculated comparing the risk and self-comparison periods. In this study, 114,035 males initiated 4vHPV vaccine and received 202,737 doses. Using the 60-day time window, 5 outcomes had significantly elevated RRs after accounting for multiple comparisons: ear conditions (RR 1.28, 95% CI 1.03–1.59); otitis media and related conditions (RR 1.65, 95% CI 1.09–2.54); cellulitis and abscess of arm (RR 2.17, 95% CI 1.06–4.72); intracranial injury (RR 1.23, 95% CI 1.01–1.50); and concussion (RR 1.29, 95% CI 1.05–1.59). A higher rate of allergic reactions was noted on the day of 4vHPV vaccine receipt compared to other vaccines (21.07 events per 10,000 doses, 95% CI 18.89–23.44 versus 11.44 per 10,000 doses, 95% CI 9.84–13.22). A higher incidence rate of VTE was observed following vaccination but this association was not significant (RR 2.17, 95% CI 0.35–22.74). The 4vHPV vaccine was associated with same-day allergic reactions as well as ear infections, intracranial injury, cellulitis, and concussion within 2 months after vaccination. While allergic reaction and cellulitis are consistent with the known safety profile of 4vHPV vaccine, the association of the other outcomes were determined by an independent Safety Review Committee to be most likely a result of activities common in adolescent males that coincide with the timing of vaccination and not directly related to vaccination itself. Implications and Contributions: The study results support the general safety of routine immunization with 4vHPV vaccine among males to prevent HPV-related diseases and cancers

Validating an algorithm for multiple myeloma based on administrative data using a SEER tumor registry and medical record review

PURPOSE: Large numbers of multiple myeloma patients can be studied in real-world clinical settings using administrative databases. The validity of these studies is contingent upon accurate case identification. Our objective was to develop and evaluate algorithms to use with administrative data to identify multiple myeloma cases. METHODS: Patients aged ≥18 years with ≥1 International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code for multiple myeloma (203.0x) were identified at two study sites. At site 1, several algorithms were developed and validated by comparing results to tumor registry cases. An algorithm with a reasonable positive predictive value (PPV) (0.81) and sensitivity (0.73) was selected and then validated at site 2 where results were compared with medical chart data. The algorithm required that ICD-9-CM codes 203.0x occur before and after the diagnostic procedure codes for multiple myeloma. RESULTS: At site 1, we identified 1432 patients. The PPVs of algorithms tested ranged from 0.54 to 0.88. Sensitivities ranged from 0.30 to 0.88. At site 2, a random sample (n = 400) was selected from 3866 patients, and medical charts were reviewed by a clinician for 105 patients. Algorithm PPV was 0.86 (95% CI, 0.79-0.92). CONCLUSIONS: We identified cases of multiple myeloma with adequate validity for claims database analyses. At least two ICD-9-CM diagnosis codes 203.0x preceding diagnostic procedure codes for multiple myeloma followed by ICD-9-CM codes within a specific time window after diagnostic procedure codes were required to achieve reasonable algorithm performance

Effectiveness of BNT162b2 COVID-19 primary series vaccination in children aged 5–17 years in the United States: a cohort study

Abstract Background COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study’s objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. Methods This cohort study identified children aged 5–17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. Results There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36–40%]) and hospital/ED–diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56–65%]). VE estimates were lowest among children 5–11 years and during the Omicron-variant era. Conclusions Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED–diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. Registration The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf )