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There is an urgent need for treatments that prevent or delay development to advanced age-related macular degeneration (AMD). Drugs already on the market for other conditions could affect progression to neovascular AMD (nAMD). If identified, these drugs could provide insights for drug development targets. The objective of this study was to use a novel data mining method that can simultaneously evaluate thousands of correlated hypotheses, while adjusting for multiple testing, to screen for associations between drugs and delayed progression to nAMD. We applied a nested case-control study to administrative insurance claims data to identify cases with nAMD and risk-set sampled controls that were 1:4 variable ratio matched on age, gender, and recent healthcare use. The study population included cases with nAMD and risk set matched controls. We used a tree-based scanning method to evaluate associations between hierarchical classifications of drugs that patients were exposed to within 6 months, 7 to 24 months, or ever before their index date. The index date was the date of first nAMD diagnosis in cases. Risk-set sampled controls were assigned the same index date as the case to which they were matched. The study was implemented using Medicare data from New Jersey and Pennsylvania, and national data from IBM MarketScan Research Database. We set an a priori threshold for statistical alerting at P ≤ 0.01 and focused on associations with large magnitude (relative risks ≥ 2.0). Progression to nAMD. Of approximately 4000 generic drugs and drug classes evaluated, the method detected 19 distinct drug exposures with statistically significant, large relative risks indicating that cases were less frequently exposed than controls. These included (1) drugs with prior evidence for a causal relationship (e.g., megestrol); (2) drugs without prior evidence for a causal relationship, but potentially worth further exploration (e.g., donepezil, epoetin alfa); (3) drugs with alternative biologic explanations for the association (e.g., sevelamer); and (4) drugs that may have resulted in statistical alerts due to their correlation with drugs that alerted for other reasons. This exploratory drug-screening study identified several potential targets for follow-up studies to further evaluate and determine if they may prevent or delay progression to advanced AMD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To develop electronic algorithms for rapid, automated surveillance for herpes zoster and postherpetic neuralgia (PHN) using codified electronic health data. PATIENTS AND METHODS: We attempted to identify every case of herpes zoster and PHN arising between January 1 and December 31, 2008, within the electronic medical record of a 560,000-patient ambulatory practice using an array of diagnosis codes; intervals between herpes zoster encounters; and prescriptions for analgesics, anticonvulsants, and antidepressants. We assessed the sensitivity and positive predictive value (PPV) of each screening criterion by medical record review and then integrated multiple criteria into combination algorithms to optimize sensitivity and PPV. We applied the optimized algorithms to the practice's historical data spanning January 1, 1996, to December 31, 2008, to assess for changes in the annual incidence of PHN. RESULTS: The International Classification of Diseases, Ninth Revision, code 053 detected herpes zoster with 98% sensitivity and 93% PPV. A combination algorithm including diagnosis codes, visit intervals, and prescriptions detected PHN with 86% sensitivity and 78% PPV. Between 1996 and 2008, the age- and sex-adjusted annual incidence of PHN rose from 0.18 to 0.47 cases per 1000 patients, and the proportion of herpes zoster patients progressing to PHN rose from 5.4% to 17.6%. CONCLUSION: Novel algorithms incorporating multiple streams of electronic health data can reasonably detect herpes zoster and PHN. These algorithms could facilitate meaningful public health surveillance using electronic health data. The incidence of PHN may be increasing. [ABSTRACT FROM AUTHOR]

Background: Maps depicting the geographic variation in cancer incidence, mortality or treatment can be useful tools for developing cancer control and prevention programs, as well as for generating etiologic hypotheses. An important question with every cancer map is whether the geographic pattern seen is due to random fluctuations, as by pure chance there are always some areas with more cases than expected, or whether the map reflects true underlying geographic variation in screening, treatment practices, or etiologic risk factors.Methods: Nine different tests for spatial randomness are evaluated in very practical settings by applying them to cancer maps for different types of data at different scales of spatial resolution: breast, prostate, and thyroid cancer incidence; breast cancer treatment and prostate cancer stage in Connecticut; and nasopharynx and prostate cancer mortality in the U.S.Results: Tango's MEET, Oden's Ipop, and the spatial scan statistic performed well across all the data sets. Besag-Newell's R, Cuzick-Edwards k-NN, and Turnbull's CEPP often perform well, but the results are highly dependent on the parameter chosen. Moran's I performs poorly for most data sets, whereas Swartz Entropy Test and Whittemore's Test perform well for some data sets but not for other.Conclusions: When publishing cancer maps we recommend evaluating the spatial patterns observed using Tango's MEET, a global clustering test, and the spatial scan statistic, a cluster detection test. [ABSTRACT FROM AUTHOR]

: ObjectivesTo evaluate the geographic variation of prostate cancer incidence in Connecticut during a 15-year period: before the introduction of prostate-specific antigen (PSA) testing (1984 to 1988), during its introduction (1989 to 1993), and after its widespread adoption (1994 to 1998).: MethodsA spatial scan statistic was used to detect and test the significance of the geographic rate variation among 29,944 incident cases.: ResultsDuring 1984 to 1988, eight locations had incidence rates that differed significantly from the statewide level; for 1989 to 1993, only two locations were identified. By 1994 to 1998, a significant rate variation was noted for 10 locations around Connecticut.: ConclusionsThe observed geographic variation of incidence rates may reflect differing opportunities to uncover latent cases at given locales. [Copyright &y& Elsevier]

Highlights • In a Vaccine Safety Datalink dataset, summary measures such as cumulative exposure to vaccine doses, vaccine antigens, and aluminum in vaccines were highly correlated. The variance inflation factors were 7.14, 6.25 and 2.17 when range-scaled number of vaccine antigens , number of vaccines , and vaccine aluminum exposure were each regressed against the other two measures, respectively. • In simulation where one of the three summary measures was the true risk factor, we showed that it was very likely that an association would be detected if a summary measure other than the true risk factor was used. • In the simulations, we also showed that the empirical power to detect the association between the true risk factor and the outcome significantly decreased if the other two measures were in the model. • If one measure was a strong risk factor and the other two were weak risk factors, a multiple logistic regression model with the three summary measures would be appropriate for detecting the strong risk factor. • Correctly specifying the relationship between risk factors and the outcome was crucial. Abstract Background Summary measures such as number of vaccine antigens, number of vaccines, and vaccine aluminum exposure by the 2nd birth day are directly related to parents' concerns that children receive too many vaccines over a brief period. High correlation among summary measures could cause problems in regression models that examine their associations with outcomes. Objectives To evaluate the performance of multiple regression models using summary measures as risk factors to simulated binary outcomes. Methods We calculated summary measures for a cohort of 232,627 children born between 1/1/2003 and 9/31/2013. Correlation and variance inflation factors (VIFs) were calculated. We conducted simulations (1) to examine the extent to which an association can be detected using a summary measure other than the true risk factor; (2) to evaluate the performance of multiple regression models including true and redundant risk factors; (3) to evaluate the performance of multiple regression models when all three were risk factors; (4) to examine the performance of multiple regression models with incorrect relationship between risk factors and outcome. Results These summary measures were highly correlated. VIFs were 7.14, 6.25 and 2.17 for number of vaccine antigens, number of vaccines, and vaccine aluminum exposure, respectively. In simulations, an association would be detected if a summary measure other than the true risk factor was used. The power to detect the association between the true risk factor and outcome significantly decreased if redundant risk factors were included. When all three were risk factors, multiple regression model was appropriate to detect the stronger risk factor. Correctly specifying the relationship between risk factors and the outcome was crucial. Conclusions Multiple regression models can be used to examine the association between summary measures and outcome despite of high correlation among summary measures. It is important to correctly specify the relationship between risk factors and outcome. [ABSTRACT FROM AUTHOR]

Background: Historically, prostate cancer mortality rates have been elevated in the U.S. Northern Plains states. The purpose of this study was to investigate possible contributing factors, especially whether there was any association with crop patterns. Methods: Prostate cancer mortality rates (1950–2000) in four northern plains states (MN, MT, ND, and SD) were compared to rates for 46 other U.S. states. Within the four states, county rates in urban, less urban, and rural areas also were compared. For additional analysis, urban counties and counties with <10% of county area in crops were excluded. The average percent of county area in total cropland 1930–1950 and 1954–1974 was estimated. Using Poisson regression, we investigated whether the average percentage of county area in total cropland, 1930–1950 and 1954–1974, was associated with prostate cancer mortality rates, 1975–2000, respectively. Poisson regression analyses were also used to evaluate associations between rates and major crops, which included spring and durum wheat, winter wheat, corn, and other crops. Population centroids of the Census 2000 block groups were used to estimate the percentage of males aged 35 and older residing in close proximity to small grains crops. Results: Mortality rates were higher in rural compared to urban counties in 1950–2000 (rate ratio [RR]=1.032; 95% CI=1.001–1.063). Rates in 1950–1974 were significantly associated with production of corn and other crops in 1930–1950 (corn: RR per 10% increase=1.033, 95% CI=1.012–1.054; other crops: RR=1.042, 95% CI=1.021–1.063). Mortality rates in 1975–2000 were significantly associated with spring and durum wheat production in 1954–1974 (RR per 10% increase=1.042, 95% CI=1.017–1.067). Prostate cancer mortality rates increased as the percentage of population living within 500 m of small grains crops increased. Conclusions: Epidemiologic studies to evaluate agricultural practices are warranted to further evaluate the observed associations. [Copyright &y& Elsevier]

During the first year of the pandemic, East Asian countries have reported fewer infections, hospitalizations, and deaths from COVID-19 disease than most countries in Europe and the Americas. Our goal in this paper is to generate and evaluate hypothesis that may explain this striking fact. We consider five possible explanations: (1) population age structure (younger people tend to have less severe COVID-19 disease upon infection than older people); (2) the early adoption of lockdown strategies to control disease spread; (3) genetic differences between East Asian population and European and American populations that confer protection against COVID-19 disease; (4) seasonal and climactic contributors to COVID-19 spread; and (5) immunological differences between East Asian countries and the rest of the world. The evidence suggests that the first four hypotheses are unlikely to be important in explaining East Asian COVID-19 exceptionalism. Lockdowns, in particular, fail as an explanation because East Asian countries experienced similarly good infection outcomes despite vast differences in lockdown policies adopted by different countries to control the COVID-19 epidemic. The evidence to date is consistent with our fifth hypothesis – pre-existing immunity unique to East Asia – but there are still essential parts of this story left for scientists to check. [ABSTRACT FROM AUTHOR]

Despite the prevalence and negative impact of posttraumatic stress disorder (PTSD), there are few medications approved by the U.S. Food and Drug Administration for treatment, and approved medications do not work well enough. We leveraged large-scale electronic health record data to identify existing medications that may be repurposed as PTSD treatments. We constructed a mechanistic tree of all Food and Drug Administration–approved medications and used the tree-based scan statistic to identify medications associated with greater than expected levels of clinically meaningful improvement in PTSD symptoms using electronic health record data from the U.S. Department of Veterans Affairs. Our cohort included patients with a diagnosis of PTSD who had repeated symptom measurements using the PTSD Checklist over a 20-year period (N = 168,941). We calculated observed numbers based on patients taking each drug or mechanistically related class of drugs and the expected numbers based on the tree as a whole. Medications typically used to treat PTSD, such as the Food and Drug Administration–approved agent sertraline, were associated with improvement in PTSD symptoms, but the effects were small. Several, but not all, direct-acting antivirals used in the treatment of hepatitis C virus demonstrated a strong association with PTSD improvement. The finding was robust to a sensitivity analysis excluding patients who received established PTSD treatments, including trauma-focused psychotherapy, concurrent with hepatitis treatment. Our exploratory approach both demonstrated findings that are consistent with what is known about pharmacotherapy for PTSD and uncovered a novel class of medications that may improve PTSD symptoms. [ABSTRACT FROM AUTHOR]

Abstract: Using a new sequential analytic method, the safety of tetanus–diphtheria–acellular pertussis (Tdap) vaccine was monitored weekly among subjects aged 10–64 years during 2005–2008. Encephalopathy–encephalitis–meningitis, paralytic syndromes, seizures, cranial nerve disorders, and Guillain-Barré syndrome were selected as outcomes based on previous reports and biologic plausibility. The risk following Tdap was not significantly higher than the risk after Td. Statistical power was sufficient to detect a relative risk of 4–5 for Guillain-Barré syndrome and 1.5–2 for the other outcomes. This study provides reassurance that Tdap is similar in safety to Td regarding the outcomes studied and supports the viability of sequential analysis for post-licensure vaccine safety monitoring. [Copyright &y& Elsevier]

Abstract: Electronic medical records of a large veterinary practice were used for surveillance of potential space–time clustering of adverse events associated with rabies vaccination in dogs. The study population was 257,564 dogs vaccinated in 169 hospitals in 13 US metropolitan areas during a 24-month period. Using a scan statistic for population rate data, significant space–time clusters were identified involving the Atlanta and Tampa/St. Petersburg areas during a 4-month period. Separate spatial–temporal analyses of these cities using coordinates for individual address coordinates identified one significant patient cluster (P =0.002), associated with a 23.26km-radius area in Atlanta (20 adverse events in 702 dogs; 2.85%) from November 2002 through February 2003. This percentage of adverse events was significantly increased after adjustment for host-related factors and the number of concurrent vaccinations. [Copyright &y& Elsevier]

Heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs), formed in temperature and time-dependent manners during cooking of meat, may increase the risk of certain cancers. As these compounds could be carcinogenic for the pancreas, we assessed meat intake, preparation methods, and doneness preferences as risk factors for exocrine pancreatic cancer.In a case-control study (cases=193, controls=674), subjects provided information on their usual meat intake and how it was cooked, e.g. fried, grilled or barbecued (BBQ), etc. Meat doneness preferences were measured using photographs that showed internal doneness and external brownness with a numerical scale. Data were analyzed with unconditional logistic regression. Odds ratios (ORs) increased with increased intake of grilled/BBQ red meat in an analysis adjusted for age, sex, smoking, education, race, and diabetes. Based on amount of BBQ meat consumed, the OR and 95% confidence interval (CI) for the fifth quintile relative to the reference group (quintiles 1 and 2) was 2.19 (1.4, 3.4). Findings were not substantively changed by further adjustment for calories, total fat, fruit and vegetables, or alcohol consumption (from a food frequency questionnaire (FFQ)). Other meat variables did not show statistically significant associations with risk nor did they substantively alter the findings for BBQ. These included total meat, processed meat, total red meat, total white meat, total broiled meat, total fried meat, or total meat cooked by means other than grilling. We conclude that grilled red meat intake is a risk factor for pancreatic cancer and that method of meat preparation in addition to total intake is important in assessing the effects of meat consumption in epidemiologic studies. [Copyright &y& Elsevier]

In the response to COVID-19, countries have implemented response strategies along a continuum of population- and venue-level specificity ranging from suppression to mitigation strategies. Suppression strategies generally include population-wide shelter-in-place mandates or lockdowns, closure of nonessential physical venues, travel bans, testing and contact tracing, and quarantines. Sweden followed a mitigation strategy focused on risk-tailored approaches to mitigate specific acquisition risks among the elderly, minimizing the disruption to education and the delivery of other health care services, and recommendations for social distancing to minimize the disease burden. To date, Sweden has reported higher case counts and attributable mortality than other Scandinavian countries and lower than other Northern European countries. However, there are several limitations with comparison given heterogeneity in testing strategies, suspected and confirmed case definitions, and assessment of attributable mortality. The decisions in Sweden also reflect social priorities such as equity being a foundational principle of Swedish social systems. Consistently, in-person education for those aged less than 16 years continued throughout. Notably, the mitigation strategy did not eliminate the inequitable impacts of COVID-19 cases and mortality in Sweden with higher-exposure and generally lower-income occupations being associated with higher risks intersecting with these communities often residing in more dense multigenerational households. From January 1 to November 15, there has been a 1.8% increase in all-cause mortality in 2020 compared with the average of 2015-2019, representing an excess of 14.3 deaths per 100,000 population. However, the final assessment of excess deaths in Sweden in 2020 including stratification by age and integration of secular trends can only be calculated in the coming years. In response to increasing cases in the fall of 2020, Sweden has continued to leverage business-oriented regulations and public-oriented guidelines for social distancing rather than police-enforced mandates. Ultimately, pandemics present no winners. Countries have implemented a range of different COVID-19 prevention and mitigation strategies responsive to their own priorities and legal systems including equity and the balancing of competing health priorities. Given these varied approaches, countries that pursued elimination, suppression, or mitigation strategies can collaboratively learn from both successes and challenges of the different strategies to inform COVID-19 and future pandemic responses. [ABSTRACT FROM AUTHOR]

After the Food and Drug Administration (FDA) licensed quadrivalent human papillomavirus vaccine (HPV4) in 2006, reports suggesting a possible association with venous thromboembolism (VTE) emerged from the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink. Our objective was to determine whether HPV4 increased VTE risk. The subjects were 9−26-year-old female members of five data partners in the FDA's Mini-Sentinel pilot project receiving HPV4 during 2006−2013. The outcome was radiologically confirmed first-ever VTE among potential cases identified by diagnosis codes in administrative data during Days 1−77 after HPV4 vaccination. With a self-controlled risk interval design, we compared counts of first-ever VTE in risk intervals (Days 1−28 and Days 1−7 post-vaccination) and control intervals (Days 36−56 for Dose 1 and Days 36−63 for Doses 2 and 3). Combined hormonal contraceptive use was treated as a potential confounder. The main analyses were: (1) unadjusted for time-varying VTE risk from contraceptive use, (2) unadjusted but restricted to cases without such time-varying risk, and (3) adjusted by incorporating the modeled risk of VTE by week of contraceptive use in the analysis. Of 279 potential VTE cases identified following 1,423,399 HPV4 doses administered, 225 had obtainable charts, and 53 were confirmed first-ever VTE. All 30 with onsets in risk or control intervals had known risk factors for VTE. VTE risk was not elevated in the first 7 or 28 days following any dose of HPV in any analysis (e.g. relative risk estimate (95% CI) from both unrestricted analyses, for all-doses, 28-day risk interval: 0.7 (0.3−1.4)). Temporal scan statistics found no clustering of VTE onsets after any dose. Thus, we found no evidence of an increased risk of VTE associated with HPV4 among 9−26-year-old females. A particular strength of this evaluation was its control for both time-invariant and contraceptive-related time-varying potential confounding. [ABSTRACT FROM AUTHOR]

Abstract: Background: In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9–26 year-old female vaccine recipients between August 2006 and October 2009. Methods: Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan–Barré Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis. Results: A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9–17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization). Conclusions: In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted. [Copyright &y& Elsevier]

Background: The emergence of pandemic H1N1 influenza virus in early 2009 prompted the rapid licensure and use of H1N1 monovalent inactivated (MIV) and live, attenuated (LAMV) vaccines separate from seasonal trivalent inactivated (TIV) and live, attenuated (LAIV) influenza vaccines. A robust influenza immunization program in the U.S. requires ongoing monitoring of potential adverse events associated with vaccination. Purpose: To prospectively conduct safety monitoring of H1N1 and seasonal influenza vaccines during the 2009–2010 season. Methods: The Vaccine Safety Datalink (VSD) Project monitors ∼9.2 million members in eight U.S. medical care organizations. Electronic data on vaccines and pre-specified adverse events were updated and analyzed weekly for signal detection from November 2009 to April 2010 using either a self-controlled design or a current versus historical comparison. Statistical signals were further evaluated using alternative approaches to identify temporal clusters and to control for time-varying confounders. Results: As of May 1, 2010, a total of 1,345,663 MIV, 267,715 LAMV, 2,741,150 TIV, and 157,838 LAIV doses were administered in VSD. No significant associations were noted during sequential analyses for Guillain–Barré syndrome, most other neurologic outcomes, and allergic and cardiac events. For MIV, a statistical signal was observed for Bell''s palsy for adults aged ≥25 years on March 31, 2010, using the self-controlled approach. Subsequent analyses revealed no significant temporal cluster. Case-centered logistic regression adjusting for seasonality demonstrated an OR for Bell''s palsy of 1.26 (95% CI=0.97, 1.63). Conclusions: No major safety problems following H1N1 or seasonal influenza vaccines were detected in the 2009–2010 season in weekly sequential analyses. Seasonality likely contributed to the Bell''s palsy signal following MIV. Prospective safety monitoring followed by rigorous signal refinement is critical to inform decision-making by regulatory and public health agencies. [Copyright &y& Elsevier]

Background: Missing data in cancer surveillance records are common; however, little information exists on the types of cases most likely to have missing data, or how missing data influence research or policy. Two clinical elements often missing in surveillance data are histologic grade and stage of disease. Missing data are either not clinically ascertained or not successfully abstracted. Methods: Prostate cancer cases (N=22,217) reported to the Maryland Cancer Registry during 1992–1997 were geocoded by residence and analyzed. Multi-level logistic regression was used to examine case attributes and area-level demographic, economic, and health services characteristics predictive of either missing stage or grade. A scanning statistic was used to explore geographic clustering of high and low rates of missing stage and grade within the state, before and after adjustment for significant variables from multi-level models. Results: Older age, black race, missing grade, and higher county-level median income increased the likelihood of missing stage, whereas more recent year of diagnosis, higher blockgroup-level median income, and county-level rurality decreased the likelihood. Older age, missing or later stage, higher blockgroup-level median income, and more urologists per case in one’s county of residence increased the likelihood of missing tumor grade, and more recent year of diagnosis, higher county-level median income, and rurality decreased the likelihood. Adjustment reduced statistically significant clusters of missing stage from six to two, and clusters of missing grade from three to zero. Conclusions: Results suggest systematic influences on missing stage and grade, which could be investigated with case–control follow-back studies. [Copyright &y& Elsevier]

Purpose: To examine geographic variation in survival time of men diagnosed with prostate cancer, adjusted for patient and disease characteristics. Method: Survival times for a geographically referenced database of 27,189 incident prostate cancer cases (ICD-O-2: C61.9) from Connecticut, 1984–1998, were evaluated using a newly developed extension of the spatial scan statistic for survival data. Results: Statewide, median survival time was 4.6 years following diagnosis. Age-adjusted survival times across most locales around Connecticut did not differ markedly from the statewide pattern, but our analysis revealed 3 zones with noteworthy differences. Analysis of survival times adjusted for age as well as tumor grade and stage produced only two locations with significant results, and further adjustment for racial composition of cases yielded only one location with significant distinct (lower) survival times. Among cases within that place, the likelihood of dying was estimated to be 1.39-times greater than that of cases different from those diagnosed elsewhere around the state (p = 0.009). Conclusion: The prognosis for men with prostate cancer may differ, in part, by virtue of where they live when diagnosed. Measuring geographic differences in survival time should facilitate the targeting of clinical and ancillary services to persons at high risk of poor outcomes. [Copyright &y& Elsevier]