Time-lag Bias Research Articles

Publication bias, time-lag bias, and place-of-publication bias in social intervention research: An exploratory study of 527 Swedish articles published between 1990-2019.

Publication and related biases constitute serious threats to the validity of research synthesis. If research syntheses are based on a biased selection of the available research, there is an increased risk of producing misleading results. The purpose fo this study is to explore the extent of positive outcome bias, time-lag bias, and place-of-publication bias in published research on the effects of psychological, social, and behavioral interventions. The results are based on 527 Swedish outcome trials published in peer-reviewed journals between 1990 and 2019. We found no difference in the number of studies reporting significant compared to non-significant findings or in the number of studies reporting strong effect sizes in the published literature. We found no evidence of time-lag bias or place-of-publication bias in our results. The average reported effect size remained constant over time as did the proportion of studies reporting significant effects.

A systematic review and meta-analysis of observational studies of the association between the use of incretin-based therapies and the risk of pancreatic cancer.

Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of incretin-based therapies, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists. This possibility has been somewhat mitigated by the null findings meta-analyses of randomized controlled trials, but the usefulness of their findings was hampered by serious shortcomings of lack of power and representativeness. These shortcomings can typically be addressed by observational studies, but observational studies on the topic have yielded conflicting findings. A systematic review and meta-analysis of observational studies was performed to qualitatively and quantitatively appraise the totality of evidence on the association between the use of incretin-based therapies and the risk of pancreatic cancer in routine clinical practice. The PubMed, Web of Science, Embase, and Google Scholar databases were searched. The study quality was appraised using the ROBINS-I tool and based on the presence of pharmacoepidemiology biases. A random-effects model was used to estimate the summary relative risks with corresponding CIs. A total of 14 studies were included. The qualitative assessment revealed that all studies had inadequate follow-up (≤5 years), 12 studies were suspected to suffer from time-lag bias (due to inappropriate choice of comparator group) to varying extent, five studies included prevalent users, five studies did not implement exposure lag period, five studies had a serious risk of bias due to confounding, and one study had a time-window bias. The quantitative assessment showed no indication of an increased risk when all studies were pooled together (RR 1.04, 95% CI 0.87, 1.24) and when the analysis was restricted to the studies with the least bias (RR 0.77, 95% CI 0.51, 1.17). However, the pooled RRs were more frequently higher in the studies with less rigorous design and analysis. Specifically, a tendency toward an increased risk was observed in the studies with (RR 1.34, 95% CI 1.04, 1.72) or possibly with (RR 1.10, 95% CI 0.89, 1.36) time-lag bias, in the studies that did not apply (RR 1.23, 95% CI 0.93, 1.63) or with potentially inadequate exposure lag period of 6months (RR 1.13, 95% CI 0.66, 1.94), in the studies that inappropriate comparator group of a combination of unspecified (RR 1.49, 95% CI 1.25, 1.78) or non-insulin (RR 1.15, 95% CI 0.93, 1.42) antidiabetic drugs, and in the studies with serious risk of bias due to confounding (RR 1.18, 95% CI 0.56, 2.49). In summary, the totality of evidence from observational studies does not support the claim that the use of incretin-based therapies is associated with an increased risk of pancreatic cancer in routine clinical practice. The increased risk of pancreatic cancer observed in observational studies reflects bias resulting from suboptimal methodological approaches, which need to be avoided by future studies.

Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases.

Background:When studying drug effects using observational data, time-related biases may exist and result in spurious associations. Numerous observational studies have investigated metformin and dementia risk, but have reported inconsistent findings, some of which might be caused by unaddressed time-related biases. Immortal time bias biases the results toward a “protective” effect, whereas time-lag and time-window biases can lead to either a “detrimental” or “protective” effect.Objective:To conduct a systematic review examining time-related biases in the literature on metformin and dementia.Methods:The electronic databases PubMed, Web of Science, and ProQuest were searched for the terms “Metformin” AND (“dementia” OR “Alzheimer’s Disease” OR “cognitive impairment"). These databases were searched from inception through 09/24/2021. Only English language articles and human research were eligible.Results:Seventeen studies were identified: thirteen cohort studies, two case-control studies, and two nested case-control studies. Eleven (64.7%) studies reported a reduced risk of dementia associated with metformin use; two (11.8%) suggested metformin increased dementia risk, while four (23.5%) concluded no significant associations. Eight (61.5%) of thirteen cohort studies had immortal time bias or did not clearly address it. Fifteen (88.2%) of seventeen reviewed studies had time-lag bias or did not clearly address it. Two (50.0%) of four case-control studies did not explicitly address time-window bias. The studies that addressed most biases concluded no associations between metformin and dementia risk.Conclusion:None of the reviewed studies clearly addressed relevant time-related biases, illustrating time-related biases are common in observational studies investigating the impact of anti-diabetic medications on dementia risk.

Challenges and opportunities in real-world evidence on the renal effects of sodium-glucose cotransporter-2 inhibitors.

With increasing population aging and prevalence of type 2 diabetes (T2D) worldwide, prevention of diabetic complications remains a major unmet need. While cardiovascular outcomes of diabetes are improving over time, diabetic kidney disease (DKD) still leads to an exceedingly high rate of end‐stage kidney disease (ESKD). A game‐changing opportunity is offered by treatment with sodium‐glucose cotransporter‐2 (SGLT2) inhibitors. Randomized controlled trials (RCTs) have indisputably shown that SGLT2 inhibitors reduce the rate of DKD progression, the decline in estimated glomerular filtration rate (eGFR), and the development of ESKD. In parallel, SGLT2 inhibitors improve cardiovascular outcomes, especially the risk of hospitalization for heart failure. Real‐world studies (RWSs) have largely confirmed the findings of RCTs in broader populations of subjects with T2D followed under routine care. In the present paper, we review RWSs exploring the renal effects of SGLT2 inhibitors and highlight the most critical challenges that can be encountered in designing and conducting such studies. Channelling bias (confounding by indication), time‐lag bias, conditioning on the future, database heterogeneity, linearity of eGFR change over time, and duration of observation are critical issues that may undermine the robustness of RWS findings. We then elaborate on the new opportunities to overcome such limitations by describing the design and objectives of the DARWIN (DApagliflozin Real‐World evIdeNce)‐Renal study, a new RWS promoted by the Italian Diabetes Society. Fine‐tuning of methods for comparative observational research will improve evidence derived from RWSs on the renal effects of SGLT2 inhibitors, aiding the evolving discussion regarding the place of SGLT2 inhibitors in T2D treatment algorithms in different stages of DKD.

Immunization coverage and its determinant factors among children aged 12\u201323\u2009months in Ethiopia: a systematic review, and Meta- analysis of cross-sectional studies

BackgroundImmunization is the process by which a person is made immune or resistant to an infectious disease, typically by the administration of vaccine. Vaccination coverage for other single vaccines ranged from 49.1% for PCV to 69.2% for BCG vaccine. The vaccination coverage for basic vaccinations was 39.7% in Ethiopia. There have been epidemiological studies available on immunization in Ethiopia. Yet, these studies revealed a wide variation over time and across geographical areas. This systematic review and Meta-analysis aim to estimate the overall immunization coverage among 12–23 months children in Ethiopia.MethodsCross-sectional studies that reported on immunization coverage from 2003 to August 2019 were systematically searched. Searches were conducted using PubMed, Google Scholar, Cochrane library, and gray literature. Information was extracted using a standardized form of Joanna Briggs Institute. The search was updated 20 Jan 2020 to decrease time-lag bias. The quality of studies assessed using Joanna Briggs Institute cross-sectional study quality assessment criteria. I-squared statistics applied to check the heterogeneity of studies. A funnel plot, Begg’s test, and Egger’s regression test was used to check for publication bias.ResultsOut of 206 studies, 30 studies with 21,672 children with mothers were included in the Meta-analysis. The pooled full immunization coverage using the random-effect model in Ethiopia was 58.92% (95% CI: 51.26–66.58%). The trend of immunization coverage was improved from time to time, but there were great disparities among different regions. Amhara region had the highest pooled fully immunized coverage, 72.48 (95%CI: 62.81–82.16). The I2 statistics was I2 = 99.4% (p = 0.0001). A subgroup meta-analysis showed that region and study years were not the sources of heterogeneity.ConclusionThis review showed that full immunization coverage in Ethiopia was 58.92% (95% CI: 51.26–66.58%). The study suggests that the child routine immunization program needs to discuss this low immunization coverage and the current practice needs revision.

Publication and related biases in health services research: a systematic review of empirical evidence

BackgroundPublication and related biases (including publication bias, time-lag bias, outcome reporting bias and p-hacking) have been well documented in clinical research, but relatively little is known about their presence and extent in health services research (HSR). This paper aims to systematically review evidence concerning publication and related bias in quantitative HSR.MethodsDatabases including MEDLINE, EMBASE, HMIC, CINAHL, Web of Science, Health Systems Evidence, Cochrane EPOC Review Group and several websites were searched to July 2018. Information was obtained from: (1) Methodological studies that set out to investigate publication and related biases in HSR; (2) Systematic reviews of HSR topics which examined such biases as part of the review process. Relevant information was extracted from included studies by one reviewer and checked by another. Studies were appraised according to commonly accepted scientific principles due to lack of suitable checklists. Data were synthesised narratively.ResultsAfter screening 6155 citations, four methodological studies investigating publication bias in HSR and 184 systematic reviews of HSR topics (including three comparing published with unpublished evidence) were examined. Evidence suggestive of publication bias was reported in some of the methodological studies, but evidence presented was very weak, limited in both quality and scope. Reliable data on outcome reporting bias and p-hacking were scant. HSR systematic reviews in which published literature was compared with unpublished evidence found significant differences in the estimated intervention effects or association in some but not all cases.ConclusionsMethodological research on publication and related biases in HSR is sparse. Evidence from available literature suggests that such biases may exist in HSR but their scale and impact are difficult to estimate for various reasons discussed in this paper.Systematic review registrationPROSPERO 2016 CRD42016052333.

Effect Declines Are Systematic, Strong, and Ubiquitous: A Meta-Meta-Analysis of the Decline Effect in Intelligence Research.

Empirical sciences in general and psychological science in particular are plagued by replicability problems and biased published effect sizes. Although dissemination bias-related phenomena such as publication bias, time-lag bias, or visibility bias are well-known and have been intensively studied, another variant of effect distorting mechanisms, so-called decline effects, have not. Conceptually, decline effects are rooted in low initial (exploratory) study power due to strategic researcher behavior and can be expected to yield overproportional effect declines. Although decline effects have been documented in individual meta-analytic investigations, systematic evidence for decline effects in the psychological literature remains to date unavailable. Therefore, we present in this meta-meta-analysis a systematic investigation of the decline effect in intelligence research. In all, data from 22 meta-analyses comprising 36 meta-analytical and 1,391 primary effect sizes (N = 697,000+) that have been published in the journal Intelligence were included in our analyses. Two different analytic approaches showed consistent evidence for a higher prevalence of cross-temporal effect declines compared to effect increases, yielding a ratio of about 2:1. Moreover, effect declines were considerably stronger when referenced to the initial primary study within a meta-analysis, yielding about twice the magnitude of effect increases. Effect misestimations were more substantial when initial studies had smaller sample sizes and reported larger effects, thus indicating suboptimal initial study power as the main driver of effect misestimations in initial studies. Post hoc study power comparisons of initial versus subsequent studies were consistent with this interpretation, showing substantially lower initial study power of declining, than of increasing effects. Our findings add another facet to the ever accumulating evidence about non-trivial effect misestimations in the scientific literature. We therefore stress the necessity for more rigorous protocols when it comes to designing and conducting primary research as well as reporting findings in exploratory and replication studies. Increasing transparency in scientific processes such as data sharing, (exploratory) study preregistration, but also self- (or independent) replication preceding the publication of exploratory findings may be suitable approaches to strengthen the credibility of empirical research in general and psychological science in particular.

Statistical significance did not affect time to publication in non-Cochrane systematic reviews: a metaepidemiological study

ObjectivesThe objective of the study was to investigate time-lag bias based on statistical significance in findings in non-Cochrane systematic reviews (SRs) and explore barriers to publication for review authors. Study Design and SettingWe included SRs of randomized controlled trials with completed analyses for protocols registered in the international prospective register of systematic reviews (PROSPERO) by the end of 2014. To obtain unpublished information, we sent questionnaires regarding barriers to publication of SRs to all authors between May and November 2018 and examined the association between the statistical significance of SR findings and time to acceptance. ResultsAmong the 241 SR authors contacted, 141 (58%) responded, of whom 103 met the eligibility criteria and agreed to participate. Ninety-three (90%) of the protocols had been published as journal articles and 11 (11%) remained unpublished. Statistical significance was not significantly associated with time to acceptance (adjusted hazard ratio, 1.36; 95% confidence interval, 0.84 to 2.19). The authors reported lack of time (52%), rejection by journals (42%), duplication of similar topics (42%), and nonsignificant results (29%) as barriers to publication of SRs. ConclusionWe found no convincing evidence of time-lag bias based on statistical significance in the findings among non-Cochrane SRs registered in the PROSPERO.

Time-dependent biases in observational studies of comparative effectiveness research in rheumatology. A methodological review

ObjectiveTo assess to what extent time-dependent biases (ie, immortal time bias (ITB) and time-lag bias (TLB)) occur in the latest rheumatology observational studies, describe their main mechanisms and increase the...

Hepatitis B virus infection among pregnant women in Ethiopia: a systematic review and Meta-analysis of prevalence studies

BackgroundThere are several epidemiological studies available on hepatitis B virus among pregnant women in Ethiopia. These individual studies revealed wide variation over time and across geographical areas. The aim of this systematic review and Meta-analysis is to estimate the overall prevalence of hepatitis B virus infection among pregnant women in Ethiopia.MethodsA comprehensive search of electronic databases including PubMed, Popline, Lalicus, Ovid, MedNar, African Journal Online (AJOL) and advanced Google Scholar was conducted regardless of publication year from August 30, 2017 to September 25, 2017. The search was updated on January 02, 2018 to minimize time-lag bias. The methodological qualities of included studies were assessed using Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instruments.ResultsOut of 103 studies, 17 studies with a total of 5629 pregnant women were included in the Meta-analysis. The pooled prevalence of hepatitis B virus infection among pregnant women using random-effect model was 4.7%(95% CI 4.0–5.4%). The I2 statistics was I2 = 37.9%(p = 0.0575). Even though significant heterogeneity among studies was not detected, the I2 = 37.9% suggests medium heterogeneity. A subgroup Meta-analysis showed that study site, region, mean/median sample size, hepatitis B virus screening methods and methodological quality were not source of heterogeneity (p-difference > 0.05).ConclusionThis review shows an intermediate level of hepatitis B virus infection among pregnant women in Ethiopia. In addition to the current practice of child vaccination, routine and universal antenatal hepatitis B virus screening program need to be implemented.

Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias?

Two recent observational studies reported a remarkably lower rate of all-cause death associated with sodium-glucose cotransporter 2 inhibitor (-SGLT2i) use in all patients with type 2 diabetes and not only those at increased cardiovascular risk. The >50% lower mortality rates reported in these studies are much greater than those found in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and CANagliflozin cardioVascular Assessment Study (CANVAS) randomized trials. We show that these observational studies are affected by time-related biases, including immortal time bias and time-lag bias, which tend to exaggerate the benefits observed with a drug. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study, based on 166,033 users of SGLT2i and 1,226,221 users of other glucose-lowering drugs (oGLD) identified from health care databases of six countries, was affected by immortal time bias. Indeed, the immortal time between the first oGLD prescription and the first SGLT2i prescription was omitted from the analysis, which resulted in increasing the rate of death in the oGLD group and thus producing the appearance of a lower risk of death with SGLT2i use. The Swedish study compared 10,879 SGLT2i/dipeptidyl peptidase 4 inhibitor (DPP-4i) users with 10,879 matched insulin users. Such comparisons involving second-line therapies with a third-line therapy can introduce time-lag bias, as the patients may not be at the same stage of diabetes. This bias is compounded by the fact that the users of insulin had already started their insulin before cohort entry, unlike the new users of SGLT2i. Finally, the study also introduces immortal time bias with respect to the effects of SGLT2i relative to DPP-4i. In conclusion, the >50% lower rate of death with SGLT2i in type 2 diabetes reported by two recent observational studies is likely exaggerated by immortal time and time-lag biases. It thus remains uncertain whether the benefit seen with empagliflozin in the EMPA-REG OUTCOME trial applies to all SGLT2i and to all patients with type 2 diabetes, not only those at increased cardiovascular risk. While observational studies can provide crucial real-world evidence for the effects of medications, they need to be carefully conducted to avoid such major time-related biases.

Association between statistical significance and time to publication among systematic reviews: a study protocol for a meta-epidemiological investigation

IntroductionMany studies have indicated the impact of bias in dissemination and publication in medical research. Existence of such bias among clinical trials has been repeatedly pointed out, but it has...

Further exploration of dissemination bias in qualitative research required to facilitate assessment within qualitative evidence syntheses

ObjectivesTo conceptualise and discuss dissemination bias in qualitative research. ResultsIt is likely that the mechanisms leading to dissemination bias in quantitative research, including time lag, language, gray literature, and truncation bias also contribute to dissemination bias in qualitative research. These conceptual considerations have informed the development of a research agenda. ConclusionFurther exploration of dissemination bias in qualitative research is needed, including the extent of non-dissemination and related dissemination bias, and how to assess dissemination bias within qualitative evidence syntheses. We also need to consider the mechanisms through which dissemination bias in qualitative research could occur to explore approaches for reducing it.

No difference found in time to publication by statistical significance of trial results: a methodological review.

ObjectiveTime-lag from study completion to publication is a potential source of publication bias in randomised controlled trials. This study sought to update the evidence base by identifying the effect of the statistical significance of research findings on time to publication of trial results.DesignLiterature searches were carried out in four general medical journals from June 2013 to June 2014 inclusive (BMJ, JAMA, the Lancet and the New England Journal of Medicine).SettingMethodological review of four general medical journals.ParticipantsOriginal research articles presenting the primary analyses from phase 2, 3 and 4 parallel-group randomised controlled trials were included.Main outcome measuresTime from trial completion to publication.ResultsThe median time from trial completion to publication was 431 days (n = 208, interquartile range 278–618). A multivariable adjusted Cox model found no statistically significant difference in time to publication for trials reporting positive or negative results (hazard ratio: 0.86, 95% CI 0.64 to 1.16, p = 0.32).ConclusionIn contrast to previous studies, this review did not demonstrate the presence of time-lag bias in time to publication. This may be a result of these articles being published in four high-impact general medical journals that may be more inclined to publish rapidly, whatever the findings. Further research is needed to explore the presence of time-lag bias in lower quality studies and lower impact journals.

Cancer randomized trials showed that dissemination bias is still a problem to be solved

ObjectiveThe objective of the present study was to determine the publication rate of cancer randomized controlled trial (RCTs) and to analyze the determinants of the publication, as well as to estimate the possible existence of a location and time lag bias. We also described the bibliometric characteristics of the publications. Study design and SettingWe conducted an observational study that identified publications resulting from RCTs involving cancer-related drug products. These studies were authorized and registered by the Spanish Agency of Medicines and Medical Devices between 1999 and 2003. ResultsWe identified 168 publications of 303 RCTs, resulting in a publication rate of 55.4% after a mean follow-up of 12 years. The only factor associated to the likelihood of nonpublication was the study setting favoring only national RCTs (odds ratio 2.7; 95% confidence interval 1.5–4.8). Type of sponsor did not seem to be associated, although the largest volume of nonpublished trials is international, industry-sponsored. Positive results seemed to be associated to a publication in a higher impact factor journal and a shorter time-to-publication. ConclusionsAbout half of the cancer RCTs during the target period have not been published. The national setting is a factor associated to nonpublication, whereas the direction of results determines its dissemination (impact factor and timely publication).

Improving Precision and Accuracy of Isotope Ratios from Short Transient Laser Ablation-Multicollector-Inductively Coupled Plasma Mass Spectrometry Signals: Application to Micrometer-Size Uranium Particles.

The isotope drift encountered on short transient signals measured by multicollector inductively coupled plasma mass spectrometry (MC-ICPMS) is related to differences in detector time responses. Faraday to Faraday and Faraday to ion counter time lags were determined and corrected using VBA data processing based on the synchronization of the isotope signals. The coefficient of determination of the linear fit between the two isotopes was selected as the best criterion to obtain accurate detector time lag. The procedure was applied to the analysis by laser ablation-MC-ICPMS of micrometer sized uranium particles (1-3.5 μm). Linear regression slope (LRS) (one isotope plotted over the other), point-by-point, and integration methods were tested to calculate the (235)U/(238)U and (234)U/(238)U ratios. Relative internal precisions of 0.86 to 1.7% and 1.2 to 2.4% were obtained for (235)U/(238)U and (234)U/(238)U, respectively, using LRS calculation, time lag, and mass bias corrections. A relative external precision of 2.1% was obtained for (235)U/(238)U ratios with good accuracy (relative difference with respect to the reference value below 1%).

Technical note: Time lag correction of aquatic eddy covariance data measured in the presence of waves

Abstract. Extracting benthic oxygen fluxes from eddy covariance time series measured in the presence of surface gravity waves requires careful consideration of the temporal alignment of the vertical velocity and the oxygen concentration. Using a model based on linear wave theory and measured eddy covariance data, we show that a substantial error in flux can arise if these two variables are not aligned correctly in time. We refer to this error in flux as the time lag bias. In one example, produced with the wave model, we found that an offset of 0.25 s between the oxygen and the velocity data produced a 2-fold overestimation of the flux. In another example, relying on nighttime data measured over a seagrass meadow, a similar offset reversed the flux from an uptake of −50 mmol m−2 d−1 to a release of 40 mmol m−2 d−1. The bias is most acute for data measured at shallow-water sites with short-period waves and low current velocities. At moderate or higher current velocities (> 5–10 cm s−1), the bias is usually insignificant. The widely used traditional time shift correction for data measured in unidirectional flows, where the maximum numerical flux is sought, should not be applied in the presence of waves because it tends to maximize the time lag bias or give unrealistic flux estimates. Based on wave model predictions and measured data, we propose a new time lag correction that minimizes the time lag bias. The correction requires that the time series of both vertical velocity and oxygen concentration contain a clear periodic wave signal. Because wave motions are often evident in eddy covariance data measured at shallow-water sites, we encourage more work on identifying new time lag corrections.

A retrospective analysis of dissemination biases in the brief alcohol intervention literature.

This study examined dissemination and reporting biases in the brief alcohol intervention literature. We used retrospective data from 179 controlled trials included in a meta-analysis on brief alcohol interventions for adolescents and young adults. We examined whether the magnitude and direction of effect sizes were associated with publication type, identification source, language, funding, time lag between intervention and publication, number of reports, journal impact factor, and subsequent citations. Results indicated that effect sizes were larger for studies that had been funded (b = 0.14, 95% confidence interval [CI] [0.04, 0.23]), had a shorter time lag between intervention and publication (b = -0.03, 95% CI [-0.05, -.001]), and were cited more frequently (b = 0.01, 95% CI [+0.00, 0.01]). Studies that were cited more frequently by other authors also had greater odds of reporting positive effects (odds ratio = 1.10, 95% CI [1.02, 1.18]). Results indicated that time lag bias has increased recently: Larger and positive effect sizes were published more quickly in recent years. We found no evidence, however, that the magnitude or direction of effects was associated with location source, language, or journal impact factor. We conclude that dissemination biases may indeed occur in the social and behavioral science literature, as has been consistently documented in the medical literature. As such, primary researchers, journal reviewers, editors, systematic reviewers, and meta-analysts must be cognizant of the causes and consequences of these biases, and commit to engage in ethical research practices that attempt to minimize them. (PsycINFO Database Record

Metformin and cancer: mounting evidence against an association.

Metformin, a biguanide derived from the French lilac, has become the preferred first-line therapy for the treatment of type 2 diabetes (1). This drug is inexpensive, has an excellent safety profile, and can be safely combined with other antidiabetes agents (2). As a result, it has become the most widely prescribed antidiabetes drug worldwide. In addition to metformin’s well-established antidiabetes effects, there has been considerable interest in its antitumor properties. Such interest started from a short report of an observational study published in 2005 that suggested that the use of metformin was associated with a 23% decreased risk of any cancer (3). Since then, a large number of observational studies have been published with several “corroborating” a possible decreased incidence of cancer with this drug (4). In parallel, several laboratory studies have also suggested that metformin has antineoplastic activity, although doses used in such experiments were typically higher than the conventional doses used in the treatment of type 2 diabetes (5). Nonetheless, this apparent convergence of evidence from both observational and laboratory studies has led some to call for large randomized clinical trials (RCTs) of metformin in cancer prevention and treatment (6–9). However, a careful assessment of the observational studies conducted to date point to some important time-related biases that systematically exaggerated the reported antitumor effects of metformin (10). Time-related biases, such as immortal time bias, time window bias, and time lag bias, have been previously described in studies of diabetes treatment (10) and in other therapeutic areas (11–14). These biases result from not properly classifying exposure during the follow-up of a cohort study or from …

On correcting the time-lag bias in aerial-surveyed bark beetle infestation data

Bark beetles are among the main biotic hazards affecting forests worldwide. Aerial surveys are an appropriate and commonly used tool for detecting and monitoring bark beetle infestations at the landscape scale. However, a considerable time-lag in the aerial-surveyed data limits its use, e.g. for analyses which include temporary factors.This temporal lag is caused by the gradual decay of the host tree following a bark beetle attack. A change in the spectral signature in aerial imagery indicates an attack with a delay of several weeks or even months. Thus, aerial-surveyed infestation data suffer a temporal shift, i.e. infestations detected for a specific time period cannot be directly assumed to have been initiated within that same period. The present study introduces an algorithm which assigns the most probable time of Ips typographus L. attack to infestations detected by aerial surveys. To calculate the infestations initiated within a certain year x the algorithm considers the potential attack period, the assumed time-lag, as well as the date of aerial surveys and the amount of detected infestation from the years x, x−1 and x+1. The deviation between infestations detected by aerial survey and those actually initiated (as calculated by the algorithm) quantifies the correction effect, i.e. the time-lag bias. The algorithm was then applied to a data set which covers a time series of 26 consecutive years, including both managed and non-managed infestations. To account for uncertainty in the input variables or to mimic varying environments the application considers three different scenarios. Over all three scenarios results indicate substantial deviations, which may be either positive or negative. Further, deviation is shown to be affected by the length of the time-lag and the attack period, as well as by variations in survey dates and infestation frequency of consecutive years. Finally, the time-corrected infestation data provides a threefold benefit: (i) The temporal pattern of oscillating population dynamics is truly reflected. (ii) Comprehensive correlation analyses which include dynamic environmental covariates, e.g. temperature, precipitation, or antagonists, are facilitated. (iii) Aerial-surveyed and ground-surveyed monitoring data can be easily related whether within a region or between regions. In conclusion, this study increases the value of aerial-surveyed infestation data for bark beetle monitoring and research.