The role of statisticians in the response to COVID-19 in Israel: a holistic point of view.

The COVID-19 pandemic cast a dramatic spotlight on the use of data as a fundamental component of good decision-making. Evaluating and comparing alternative policies required information on concurrent infection rates and insightful analysis to project them into the future. Statisticians in Israel were involved in these processes early in the pandemic in some silos as an ad-hoc unorganized effort. Informal discussions within the statistical community culminated in a roundtable, organized by three past presidents of the Israel Statistical Association, and hosted by the Samuel Neaman Institute in April 2021. The meeting was designed to provide a forum for exchange of views on the profession's role during the COVID-19 pandemic, and more generally, on its influence in promoting evidence-based public policy. This paper builds on the insights and discussions that emerged during the roundtable meeting and presents a general framework, with recommendations, for involving statisticians and statistics in decision-making.

Dermoscopic and clinical predictors of reflectance confocal microscopy patterns of typical nevi on the back and legs: A cross-sectional study.

BACKGROUND: Nevus phenotype is a marker of melanoma risk. In vivo prediction of microscopic pattern is needed to more precisely classify nevi. OBJECTIVE: To identify dermoscopic and clinical predictors of microscopic patterns of typical nevi. METHODS: We used reflectance confocal microscopy (RCM) to classify microscopic patterns of nevi. We prospectively accrued adults presenting for periodic skin screening and imaged, with dermoscopy and RCM, 3 randomly selected nevi from the upper and lower back and lower extremity. RCM patterns were classified into ring, clod, meshwork, and composite types. Logistic regression was used to identify best predictors of RCM pattern. RESULTS: The study included 310 nevi from 112 participants (mean age 44 years; 51 women). Dermoscopic reticular pattern correlated most frequently (59.9%) with RCM ring pattern, dermoscopic globular with RCM composite (56.6%) and RCM clod (35.9%), dermoscopic complex with RCM composite (76.3%), and dermoscopic homogenous with RCM clod (50.8%). Integrating dermoscopic pattern with contour, diameter, color, and anatomic location of nevi improved prediction of microscopic patterns beyond dermoscopy alone. The dermoscopic clinical regression model correctly classified lesions to RCM ring versus RCM clod in 90% and to RCM ring versus RCM composite patterns in 81%. LIMITATIONS: The study was restricted to adults, back and lower extremities, and typical nevi. CONCLUSIONS: Integrating dermoscopic patterns with clinical attributes may improve prediction of microscopic patterns of nevi.

Correlation and the time interval over which the variables are measured - A non-parametric approach.

It is known that when one (or both) variable is multiplicative, the choice of differencing intervals (n) (for example, differencing interval of n = 7 means a weekly datum which is the product of seven daily data) affects the Pearson correlation coefficient (ρ) between variables (often asset returns) and that ρ converges to zero as n increases. This fact can cause the resulting correlation to be arbitrary, hence unreliable. We suggest using Spearman correlation (r) and prove that as n increases Spearman correlation tends to a limit which only depends on Pearson correlation based on the original data (i.e., the value for a single period). In addition, we show, via simulation, that the relative variability (CV) of the estimator of ρ increases with n and that r does not share this disadvantage. Therefore, we suggest using Spearman when one (or both) variable is multiplicative.

Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma.

OBJECTIVE: To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts. METHODS: We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers. RESULTS: Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001). CONCLUSIONS: The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD.

Driver views on speed and enforcement.

This paper reports on the results of a drivers' survey regarding the effects of speed cameras for speed enforcement in Israel. The survey was part of a larger study that accompanied the introduction of digital speed cameras. Speed camera deployment started in 2011, and till the end of 2013 twenty-one cameras were deployed in interurban road sections. Yearly surveys were taken between 2010 and 2013 in 9 gas stations near speed camera installation sites in order to capture drivers' opinions about speed and enforcement. Overall, 1993 drivers were interviewed. In terms of admitted speed behavior, 38% of the drivers in 2010, 21% in 2011, 13% in 2012 and 11% in 2013 reported that their driving speed was above the perceived posted speed limit. The proportion of drivers indicating some speed camera influence on driving decreased over the years. In addition, the majority of drivers (61%) predicted positive impact of speed cameras on safety. This result did not change significantly over the years. The main stated explanation for speed limit violations was time pressure, while the main stated explanation for respecting the posted speed was enforcement, rather than safety concerns. Linear regression and sigmoidal models were applied to describe the linkage between the reported driving speed (dependent) and the perceived posted speed (independent). The sigmoidal model fitted the data better, especially at high levels of the perceived posted speeds. That is, although the perceived posted speed increased, at some point the actual driving speed levels off (asymptote) and did not increase. Moreover, we found that the upper asymptote of the sigmoidal model decreased over the years: from 113.22 (SE=18.84)km/h in 2010 to 88.92 (SE=1.55)km/h in 2013. A wide variance in perceived speed limits suggest that drivers may not know what the speed limits really are.

Estimating the risk for conversion from mild cognitive impairment to Alzheimer's disease in an elderly Arab community.

BACKGROUND: Vascular risk factors and lack of formal education may increase the risk of Alzheimer's disease (AD). OBJECTIVE: To determine the contribution of vascular risk factors and education to the risk of mild cognitive impairment (MCI) and AD and to estimate the risk for conversion from MCI to AD. METHODS: This door-to-door survey was performed by an Arab-speaking team in Wadi Ara villages in Israel. All consenting residents aged ≥ 65 years were interviewed for medical history and underwent neurological and cognitive examinations. Individuals were cognitively classified as normal (CN), MCI, AD, vascular dementia, or unclassifiable. MCI patients were re-examined at least one year later to determine conversion to AD. The contributions of age, gender, school years, and vascular risk factors to the probability of conversion were estimated using logistic regression models. RESULTS: Of the 906 participants, 297 (33%) had MCI and 95 (10%) had AD. Older age (p = 0.0008), female gender (p = 0.023), low schooling (p < 0.0001), and hypertension (p = 0.0002) significantly accounted for risk of MCI versus CN, and diabetes was borderline (p = 0.051). The risk of AD versus CN was significantly associated with age (p < 0.0001), female gender (p < 0.0001), low schooling (p = 0.004) and hypertension (p = 0.049). Of the 231 subjects with MCI that were re-examined, 65 converted to AD. CONCLUSIONS: In this population, age, female gender, lack of formal education, and hypertension are risk factors for both AD and MCI. Conversion risk from MCI to AD could be estimated as a function of age, time interval between examinations, and hypertension.

Enzymatic MPG DNA repair assays for two different oxidative DNA lesions reveal associations with increased lung cancer risk.

DNA repair is a major mechanism for minimizing mutations and reducing cancer risk. Here, we present the development of reproducible and specific enzymatic assays for methylpurine DNA glycosylase (MPG) repairing the oxidative lesions 1,N6-ethenoadenine (εA) and hypoxanthine (Hx) in peripheral blood mononuclear cells protein extracts. Association of these DNA repair activities with lung cancer was determined using conditional logistic regression with specimens from a population-based case-control study with 96 lung cancer cases and 96 matched control subjects. The mean MPG-εA in case patients was 15.8 units/µg protein (95% CI 15.3-16.3), significantly higher than in control subjects-15.1 (14.6-15.5), *P = 0.011. The adjusted odds ratio for lung cancer associated with a one SD increase in MPG-εA activity (2.48 units) was significantly bigger than 1 (OR = 1.6, 95% CI = 1.1-2.4; *P = 0.013). When activity of OGG1, a different DNA repair enzyme for oxidative damage, was included in the model, the estimated odds ratio/SD for a combined MPG-εA-OGG1 score was 2.6 (95% CI 1.6-4.2) *P = 0.0001, higher than the odds ratio for each single assay. The MPG enzyme activity assays described provide robust functional risk biomarkers, with increased MPG-εA activity being associated with increased lung cancer risk, similar to the behavior of MPG-Hx. This underscores the notion that imbalances in DNA repair, including high DNA repair, usually perceived as beneficial, can cause cancer risk. Such DNA repair risk biomarkers may be useful for risk assessment of lung cancer and perhaps other cancer types, and for early detection techniques such as low-dose CT.

Co-occurrence of transcription and translation gene regulatory features underlies coordinated mRNA and protein synthesis.

BACKGROUND: Variability in protein levels is generated through intricate control of the different gene decoding phases. Presently little is known about the links between the various gene expression stages. Here we investigated the relationship between transcription and translation regulatory properties encoded in mammalian genes. RESULTS: We found that the TATA-box, a core promoter element known to enhance transcriptional output, is associated not only with higher mRNA levels but also with positive translation regulatory features and elevated translation efficiency. Further investigation revealed general association between transcription and translation regulatory trends. Specifically, translation inhibitory features such as the presence of upstream AUG (uAUG) and increased lengths of the 5'UTR, the coding sequence and the 3'UTR, are strongly associated with lower translation as well as lower transcriptional rate. CONCLUSIONS: Our findings reveal that co-occurrence of several gene-encoded transcription and translation regulatory features with the same trend substantially contributes to the final mRNA and protein expression levels and enables their coordination.

Temporal perspective on individual driver behavior using electronic records of undesirable events.

This paper explores In-Vehicle Data Recorders (IVDRs) information about the count of undesirable driving events (such as hard braking, lane changing, and sharp turning) of 148 individuals. The information was logged over three years and included time stamp information about the occurrence of undesirable driving events in each trip (N=573,238). The objective was to gain deeper understanding about the heterogeneity among drivers with respect to behavior change over time, the effect of trip duration and the distribution of events count. Our findings show that in some respects drivers are similar: for all drivers, the variance of the events count was larger than the mean, indicating that the negative binomial distribution is suitable to model the distribution of events count per trip. Most drivers (95%) had lower events rate during longer trips, suggesting that a 'simple' events rate index is problematic when comparing between those driving longer trips and drivers driving short trips. In addition, most drivers (87%) improved their driving behavior throughout the measurement period. However, there are important differences among drivers in terms of the frequency of behavior change and the trends in behavior over time. These findings demonstrate the need for personalized examination of individual drivers. Several tools for such personalized examination were developed and discussed in this study.

Low integrated DNA repair score and lung cancer risk.

DNA repair is a prime mechanism for preventing DNA damage, mutation, and cancers. Adopting a functional approach, we examined the association with lung cancer risk of an integrated DNA repair score, measured by a panel of three enzymatic DNA repair activities in peripheral blood mononuclear cells. The panel included assays for AP endonuclease 1 (APE1), 8-oxoguanine DNA glycosylase (OGG1), and methylpurine DNA glycosylase (MPG), all of which repair oxidative DNA damage as part of the base excision repair pathways. A blinded population-based case-control study was conducted with 96 patients with lung cancer and 96 control subjects matched by gender, age (±1 year), place of residence, and ethnic group (Jews/non-Jews). The three DNA repair activities were measured, and an integrated DNA repair OMA (OGG1, MPG, and APE1) score was calculated for each individual. Conditional logistic regression analysis revealed that individuals in the lowest tertile of the integrated DNA repair OMA score had an increased risk of lung cancer compared with the highest tertile, with OR = 9.7; 95% confidence interval (CI), 3.1-29.8; P < 0.001, or OR = 5.6; 95% CI, 2.1-15.1; P < 0.001 after cross-validation. These results suggest that pending validation, this DNA repair panel of risk factors may be useful for lung cancer risk assessment, assisting prevention and referral to early detection by technologies such as low-dose computed tomography scanning.

Prayer at midlife is associated with reduced risk of cognitive decline in Arabic women.

Midlife habits may be important for the later development of Alzheimer's disease (AD). We estimated the contribution of midlife prayer to the development of cognitive decline. In a door-to-door survey, residents aged ≥65 years were systematically evaluated in Arabic including medical history, neurological, cognitive examination, and a midlife leisure-activities questionnaire. Praying was assessed by the number of monthly praying hours at midlife. Stepwise logistic regression models were used to evaluate the effect of prayer on the odds of mild cognitive impairment (MCI) and AD versus cognitively normal individuals. Of 935 individuals that were approached, 778 [normal controls (n=448), AD (n=92) and MCI (n=238)] were evaluated. A higher proportion of cognitively normal individuals engaged in prayer at midlife [(87%) versus MCI (71%) or AD (69%) (p<0.0001)]. Since 94% of males engaged in prayer, the effect on cognitive decline could not be assessed in men. Among women, stepwise logistic regression adjusted for age and education, showed that prayer was significantly associated with reduced risk of MCI (p=0.027, OR=0.55, 95% CI 0.33-0.94), but not AD. Among individuals endorsing prayer activity, the amount of prayer was not associated with MCI or AD in either gender. Praying at midlife is associated with lower risk of mild cognitive impairment in women.

N-methylpurine DNA glycosylase and OGG1 DNA repair activities: opposite associations with lung cancer risk.

Only a minority of smokers develop lung cancer, possibly due to genetic predisposition, including DNA repair deficiencies. To examine whether inter-individual variations in DNA repair activity of N-methylpurine DNA glycosylase (MPG) are associated with lung cancer, we conducted a blinded, population-based, case-control study with 100 lung cancer case patients and 100 matched control subjects and analyzed the data with conditional logistic regression. All statistical tests were two-sided. MPG enzyme activity in peripheral blood mononuclear cells from case patients was higher than in control subjects, results opposite that of 8-oxoguanine DNA glycosylase (OGG1) DNA repair enzyme activity. For lung cancer associated with one standard deviation increase in MPG activity, the adjusted odds ratio was 1.8 (95% confidence interval [CI] = 1.2 to 2.6; P = .006). A combined MPG and OGG1 activities score was more strongly associated with lung cancer risk than either activity alone, with an odds ratio of 2.3 (95% CI = 1.4 to 3.6; P < .001). These results form a basis for a future panel of risk biomarkers for lung cancer risk assessment and prevention.

High prevalence of mild cognitive impairment and Alzheimer's disease in arabic villages in northern Israel: impact of gender and education.

The prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been well been studied in Arab populations. In a door-to-door study of all residents aged ≥ 65 years in Wadi-Ara, an Arab community in northern Israel, we estimated the prevalence of AD, MCI, and the risk of conversion to AD. Subjects were classified as cognitively normal, MCI, AD, or other based on neurological and cognitive examination (in Arabic). MCI subjects were re-examined (interval ≥ 1 year) to determine conversion to AD and contributions of age, gender, and education to the probability of conversion. Of the 944 participants (96.6% of those approached; 49.4% men), 92 (9.8%) had AD. An unusually high prevalence of MCI (n = 303, 32.1%) was observed. Since the majority of women (77.2%) had no schooling, we estimated the effect of gender on the risk of AD and MCI among subjects without schooling and of school years among men. Among subjects with no schooling (n = 452), age (p = 0.02) and female gender (p < 0.0001) were significant predictors of AD, whereas risk of MCI increased only with age (p = 0.0001). Among men (n = 318), age increased the risk (p < 0.0001), school years reduced the risk of AD (p = 0.039) and similarly for MCI [age (p = 0.0001); school years (p = 0.0007)]. Age (p = 0.013), but not gender or school years, was a significant predictor of conversion from MCI to AD (annual rate 5.7%). The prevalence of MCI and AD are unusually high in Wadi Ara, while the rate of conversion from MCI to AD is low. Yet unidentified genetic factors might underlie this observation.

An analysis of alcohol breath tests results with portable and desktop breath testers as surrogates of blood alcohol levels.

There is a perceived tradeoff between the ease of measuring alcohol in the body and the accuracy of the result. Direct tests of blood alcohol concentrations are considered the most accurate, desktop stationary breath testers based on electro-chemical infra-red technology are slightly less accurate, but accepted for evidentiary purposes in most jurisdictions, and quick portable breath testers based on fuel-cell technology are the easiest to administer but not acceptable in many courts. This study compared the accuracy of an evidentiary portable breath tester and an evidentiary desktop breath tester relative to blood alcohol concentrations. Inverse regressions were used to obtain confidence limits for the alcohol levels as read by the breath testers that would provide tradeoffs of false positives and false negatives for three levels of confidence: 95%, 96%, and 98%; corresponding to false positive values of 2.5%, 2%, and 1%, respectively. A decision tree model is offered for the optimal use of the three measures, so that portable breath testers can be sufficient for high level BrAC, stationary breath testers can be sufficient for medium level BrAC, and blood tests are recommended for still lower BrACs. The model provides quantitative BrAC threshold levels for the two most common BAC levels used to imply DWI: 50mg/dl and 80 mg/dl.

Mild cognitive impairment is associated with mild parkinsonian signs in a door-to-door study.

Mild cognitive impairment (MCI) and healthy aging have been shown to be associated with mild parkinsonian signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged ≥65 years (n=687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer's disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and rigidity) and cognitive tests. MCI subjects (n=111) were re-evaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p<0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR =1.19, 95% CI, 1.05 to 1.35, p=0.006) and higher limb bradykinesia scores (OR=1.75, 95% CI, 1.2 to 2.56, p=0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD.

Local injury of the endometrium induces an inflammatory response that promotes successful implantation.

OBJECTIVE: To study whether an injury-induced inflammation might be the mechanism underlying the favorable effect of endometrial biopsy on the implantation rate in in vitro fertilization (IVF) patients. DESIGN: Controlled clinical study. SETTING: A medical center IVF unit and a research institute. PATIENT(S): Women undergoing IVF who had previous failed treatment cycles. INTERVENTION(S): Endometrial samples were collected from two groups of patients on day 21 of their spontaneous menstrual cycle. The experimental, but not the control group underwent prior biopsy treatment on days 8 or/and 11 to 13 of that same cycle. MAIN OUTCOME MEASURE(S): Abundance of immune cells, cytokines/chemokines level, correlation between these parameters and pregnancy outcome. RESULT(S): A statistically significantly higher amount of macrophages/dendritic cells (HLA-DR+ CD11c+ cells) and elevated proinflammatory cytokines, tumor necrosis factor-α (TNF-α), growth-regulated oncogene-α (GRO-α), interleukin-15 (IL-15), and macrophage inflammatory protein 1B (MIP-1B), were detected in day-21 endometrial samples of the experimental group. A direct stimulatory effect of TNF-α on MIP-1B, GRO-α, and IL-15 messenger RNA (mRNA) expression was demonstrated. A positive correlation was found between the levels of macrophages/dendritic cells, MIP-1B expression, and TNF-α expression and the pregnancy outcome. CONCLUSION(S): A biopsy-induced inflammatory response may facilitate the preparation of the endometrium for implantation. Increased MIP-1B expression could possibly serve for prediction of implantation competence.

Visuo-motor coordination deficits and motor impairments in Parkinson's disease.

BACKGROUND: Visuo-motor coordination (VMC) requires normal cognitive executive functionality, an ability to transform visual inputs into movement plans and motor-execution skills, all of which are known to be impaired in Parkinson's disease (PD). Not surprisingly, a VMC deficit in PD is well documented. Still, it is not known how this deficit relates to motor symptoms that are assessed routinely in the neurological clinic. Such relationship should reveal how particular motor dysfunctions combine with cognitive and sensory-motor impairments to produce a complex behavioral disability. METHODS AND FINDINGS: Thirty nine early/moderate PD patients were routinely evaluated, including motor Unified Parkinson's Disease Rating Scale (UPDRS) based assessment, A VMC testing battery in which the subjects had to track a target moving on screen along 3 different paths, and to freely trace these paths followed. Detailed kinematic analysis of tracking/tracing performance was done. Statistical analysis of the correlations between measures depicting various aspects of VMC control and UPDRS items was performed. The VMC measures which correlated most strongly with clinical symptoms represent the ability to organize tracking movements and program their direction, rather than measures representing motor-execution skills of the hand. The strong correlations of these VMC measures with total UPDRS score were weakened when the UPDRS hand-motor part was considered specifically, and were insignificant in relation to tremor of the hand. In contrast, all correlations of VMC measures with the gait/posture part of the UPDRS were found to be strongest. CONCLUSIONS: Our apparently counterintuitive findings suggest that the VMC deficit pertains more strongly to a PD related change in cognitive-executive control, than to a reduction in motor capabilities. The recently demonstrated relationship between gait/posture impairment and a cognitive decline, as found in PD, concords with this suggestion and may explain the strong correlation between VMC dysfunction and gait/posture impairment. Accordingly, we propose that what appears to reflect a motor deficit in fact represents a multisystem failure, dominated by a cognitive decline.

Analysis of chemotaxis when the fraction of responsive cells is small--application to mammalian sperm guidance.

The detection of chemotaxis-related changes in the swimming behavior of mammalian spermatozoa in a spatial chemoattractant gradient has hitherto been an intractable problem. The difficulty is that the fraction of responsive cells in the sperm population is very small and that the large majority of the cells, though non-responsive, are motile too. Assessment of the chemotactic effects in a spatial gradient is also very sensitive to the quality of sperm tracking. To overcome these difficulties we propose a new approach, based on the analysis of the distribution of instantaneous directionality angles made by spermatozoa in a spatial gradient versus a no-gradient control. Although the use of this parameter does not allow identification of individual responding cells, it is a reliable measure of directionality, independent of errors in cell tracking caused by cell collisions, track crossings, and track splitting. The analysis identifies bias in the swimming direction of a population relative to the gradient direction. It involves statistical chi2 tests of the very large sample of measured angles, where the critical chi2 values are adjusted to the sample size by the bootstrapping procedure. The combination of the newly measured parameter and the special analysis provides a highly sensitive method for the detection of a chemotactic response, even a very small one.

A method with flexible and balanced control of false negatives and false positives for hit selection in RNA interference high-throughput screening assays: a statistical terminology.

Zhang suggests a new method that is flexible and controls the balance between false negatives and false positives for hit selection in RNA high-throughput screening assays. The author shows that the same decision rules and balances can be expressed by familiar statistical terms such as type I error and power and hence connects the new method to known statistical tools. (Journal of Biomolecular Screening 2008:309-311).