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We thank Witte and Visscher1 for their very interesting comments. As we discussed in our article,2 there are many alternative approaches within our conceptual framework for how exactly to correct for misclassification. We used the most simple and straightforward one for illustrative purposes, using a plain cutoff value assignment for reclassifying apparent controls to cases.2 We are more interested in promoting the concept rather than any particular technical method by which it could be implemented. In this regard, several options proposed by Witte and Visscher1 are certainly possible. We agree that it would be useful to compare the performance of these various correctional options in future studies. However, we suspect that improvements, if any, would be incremental rather than major. This situation is fairly equivalent to the use of imputed genotypes for genetic variants that have not been directly genotyped.3,4 Each genotype is imputed with a probability, not full certainty. Including these variants with a probabilistic weight (eg, proportional to the accuracy of their imputation) in theory is preferable to simply use a cutoff value and assign them the most likely genotype. However, differences between these approaches have been minimal in practice as shown in the large number of studies using imputations. Overall, a balance between computational simplicity and incremental precision should be considered. Correction for events that happen during follow-up may also be done with various techniques for modeling time-to-event processes. We do not agree with Witte and Visscher1 that death provides a good analogy to the future incidence of other phenotypes, such as age-related macular degeneration. Death is a universal outcome: everybody dies sooner or later. It is unlikely, however, that everyone would develop advanced age-related macular degeneration even if follow-up could be extended to the current limits of human longevity. For most common phenotypes to which our method may be applied, it is similarly unlikely that the phenotype would eventually occur in all persons if they lived long enough. Phenotypes would become more common, but not ubiquitous. We think that in discovering genetic variants it is useful to expect an average life expectancy, so as to discover risk factors that would make a difference in a typical lifetime. Moreover, in applying our method to different phenotypes, one has to consider the incidence density of the phenotype over age. For example, if a disease always develops before 50 years of age, then clearly there is no need to correct for misclassification if all enrolled participants are 50 years old. Conversely, if all disease develops between age 50 and 80 years, then using an uncorrected control participant aged 50 years is a poor choice. For discovery purposes, we argue that if a control has not developed the phenotype simply because he is currently 50 years old, but is expected to develop the phenotype with sufficiently high certainty (based on predictive modeling) by age 80 years, it is worth correcting this. As our simulations show, if the predictive model has high discriminating ability and the phenotype is common, the correction will be useful. We agree with Witte and Visscher1 that juxtaposing the predicted status versus the observed status could also have collateral benefits, such as the documentation of diagnostic errors in both research and clinical applications. In fact (and in contrast to age-related macular degeneration), the misclassification of cases into apparent controls for most phenotypes may be primarily due not to insufficient follow-up but rather to inaccurate diagnostic tests or suboptimal definitions of what constitutes disease. For many common diseases, diagnosis is not easy, there is lack of consensus among experts, or there are diverse sets of imperfect diagnostic criteria. We agree with Witte and Visscher that correcting for misclassification will not work if the model is not sufficiently accurate or if it is wrong—but we are not totally pessimistic about the prospects of predictive models. Models using genomic information alone may be unlikely to reach extremely high levels of discrimination for most phenotypes, with the exception of those with high heritability.5 However, composite models using both genomic and nongenomic information may have a better prospect. Age-related macular degeneration is probably the forerunner in this regard, and we suspect that the same high accuracy predictive models will become possible in the near future for other diseases.
A new method has been devised to measure directly the series collector resistance (r/SUB c/) of monolithic bipolar n-p-n transistors. The method uses the parasitic substrate p-n-p and the reverse n-p-n associated with each integrated n-p-n transistor to detect the internal collector-base voltage. The effects of temperature, conductivity modulation, and mobility on the collector resistance can be measured directly. Measurements on a range of devices indicate standard techniques such as the forced beta method measure only a fraction of the total collector resistance. The present technique yields results in good agreement with theoretically calculated values of r/SUB c/. This method is amenable to automated measurement systems.
ABSTRACT OBJECTIVE To examine whether the age distribution of COVID-19 deaths and the share of deaths in nursing homes changed in the second versus the first pandemic wave. ELIGIBLE DATA We considered all countries that had at least 4000 COVID-19 deaths occurring as of January 14, 2020, at least 200 COVID-19 deaths occurring in each of the two epidemic wave periods; and which had sufficiently detailed information available on the age distribution of these deaths. We also considered countries with data available on COVID-19 deaths of nursing home residents for the two waves. MAIN OUTCOME MEASURES Change in the second wave versus the first wave in the proportion of COVID-19 deaths occurring in people <50 years (“young deaths”) among all COVID-19 deaths and among COVID-19 deaths in people <70 years old; and change in the proportion of COVID-19 deaths in nursing home residents among all COVID-19 deaths. RESULTS Data on age distribution were available for 14 eligible countries. Individuals <50 years old had small absolute difference in their share of the total COVID-19 deaths in the two waves across 13 high-income countries (absolute differences 0.0-0.4%). Their proportion was higher in Ukraine, but it decreased markedly in the second wave. The odds of young deaths was lower in the second versus the first wave (summary odds ratio 0.80, 95% CI 0.70-0.92) with large between-country heterogeneity. The odds of young deaths among deaths <70 years did not differ significantly across the two waves (summary odds ratio 0.95, 95% CI 0.85-1.07). Eligible data on nursing home COVID-19 deaths were available for 11 countries. The share of COVID-19 deaths that were accounted by nursing home residents decreased in the second wave significantly and substantially in 8 countries (odds ratio estimates: 0.22 to 0.66), remained the same in Denmark and Norway and markedly increased in Australia. CONCLUSIONS In the examined countries, age distribution of COVID-19 deaths has been fairly similar in the second versus the first wave, but the contribution of COVID-19 deaths in nursing home residents to total fatalities has decreased in most countries in the second wave.
Sustained amenorrhea is difficult to avoid in women 32 years or older, even with very short IC courses, and alternative regimens should be considered. In younger women treated with a monthly IC regimen, sustained amenorrhea may occur predominantly in those with the recognized adverse predictors of this complication.
A T-to-C polymorphism in the 5′ promoter region of the CYP17 gene that encodes the cytochrome P450c17α has been implicated as a risk factor for prostate cancer, but individual studies have been inconclusive or controversial. Therefore we performed a meta-analysis of 10 studies (12 comparisons) with CYP17 genotyping on 2404 patients with prostate cancer and 2755 controls. Overall, the random effects odds ratio (OR) for the A2 (C) versus A1 (T) allele was 1.08 [95% confidence interval (CI), 0.95–1.22], with some between-study heterogeneity ( P = 0.04). There was no suggestion of an overall effect either in recessive or dominant modeling of A2 effects, and the comparison of A2/A2 versus A1/A1 also showed no differential susceptibility to prostate cancer (OR, 1.15; 95% CI, 0.91–1.46). No effect of A2 was seen in subjects of European descent (7 comparisons, OR, 1.04; 95% CI, 0.92–1.18, no significant between-study heterogeneity) or Asian descent (2 comparisons, OR, 1.06; 95% CI, 0.66–1.71; P = 0.02 for heterogeneity), whereas A2 increased susceptibility to prostate cancer in subjects of African descent (3 comparisons, OR, 1.56; 95% CI, 1.07–2.28; no between-study heterogeneity). Smaller studies unilaterally showed more prominent genetic effects for A2 than larger studies ( P = 0.038). The meta-analysis suggests that the CYP17 polymorphism is unlikely to increase considerably the risk of sporadic prostate cancer on a wide population basis, especially in subjects of European descent. Previously reported associations may reflect publication bias, although it is also possible that the polymorphism may be important in subjects of African descent.
The studies eligible for systematic review. (DOC 444 kb)
This paper presents a new algorithm to extract resistance values from an integrated circuit artwork description. Instead of trying to solve for the exact resistance values, heuristics are used to find an approximate solution. The algorithm first breaks the input polygons into simple pieces, and then finds the resistance through each piece. This procedure enables the extraction to be both fast and memory efficient. The heuristics used for splitting the polygons and calculating the pieces' resistance are derived from rules of electrostatics, and yield answers that are within 10 percent of the exact resistance values. The operations needed to break complex polygons into simpler pieces are very similar to other geometric operations used in artwork analysis systems.
