ObjectiveNeural tube defects (NTDs) are a preventable folate deficiency disorder; increasing folic acid intake through food fortification increases serum and red blood cell folate and reduces the risk of an NTD pregnancy. There is controversy over the blood folate level needed to achieve the full preventive effect because of discrepant study conclusions.MethodsResults from two published studies were used to determine the relationship between serum folate and NTD risk which was compared with the observed result in a randomised trial of folic acid that increased serum folate from 5 ng/mL to 44 ng/mL among women who took a 4 mg daily periconceptional folic acid supplement.ResultsBoth studies showed a proportional (logarithmic) relationship between serum folate and NTD risk without evidence of a folate threshold above which there is no further NTD risk reduction. The suggestion of a threshold is due to the incorrect interpretation of the folate-NTD risk association when plotted on arithmetic scales, which conceals the proportional relationship between the two. Also, both studies accurately estimated the observed result from the randomised trial that achieved a median serum folate level of 44 ng/mL and an 83% preventive effect. This is much higher than has been achieved with current levels of folic acid fortification with serum folate between 10 and 16 ng/mL, resulting in an approximate 20% preventive effect.ConclusionTo achieve fully effective fortification, median population serum folate levels need to be about 44 ng/mL, which would globally prevent about 250 000 NTD cases every year.

This commentary, linked to our paper in the same issue of the Journal of Medical Screening, discusses the reluctance to consider and adopt the polypill in the primary prevention of heart attacks and strokes, access to the polypill as a public health service, the formulation of the polypill in current use, its prescription as an unlicensed medicine, and what can be done to facilitate the adoption of the polypill approach as a routine public health service.

OBJECTIVE:To compare the NHS Health Check Programme with the Polypill Prevention Programme in the primary prevention of heart attacks and strokes. DESIGN:Use of published data and methodology to produce flow charts of the two programmes to determine screening performance and heart attacks and strokes prevented. SETTING:The UK population. INTERVENTION:The NHS Health Check Programme using a QRISK score on people aged 40-74 to select those eligible for a statin is compared with the Polypill Prevention Programme in people aged 50 or more to select people for a combination of a statin and three low-dose blood pressure lowering agents. In both programmes, people had no history of heart attack or stroke. MAIN OUTCOME MEASURES:In 1000 people, the number of heart attacks and strokes prevented in the two programmes. RESULTS:In the hypothetical perfect situation with 100% uptake and adherence to the screening protocol, in every 1000 persons, the NHS Health Check would prevent 287 cases of a heart attack or stroke in individuals who would gain on average about 4 years of life without a heart attack or stroke amounting to 1148 years in total, the precise gain depending on the extent of treatment for those with raised blood pressure, and 136 would be prescribed statins with no benefit. The corresponding figures for the Polypill Prevention Programme are 316 individuals who would, on average, gain 8 years of life without a heart attack or stroke, amounting to 2528 years in total, and 260 prescribed the polypill with no benefit. Based on published estimates of uptake and adherence in the NHS Health Check Programme, in practice only 24 cases per 1000 are currently benefitting instead of 287, amounting to 96 years gained without a heart attack or stroke. CONCLUSIONS:The Polypill Prevention Programme is by design simpler with the potential of preventing many more heart attacks and strokes than the NHS Health Check Programme.

ABSTRACT Introduction Neural tube defects (NTDs) are a folate deficiency disorder. NTDs are preventable; increasing folic acid intake through food fortification or use of supplements increases serum and red blood cell folate and reduces the risk of a woman having an NTD pregnancy. There is controversy over whether there is a blood folate level needed to achieve the full preventive effect because of discrepant conclusions from studies investigating the relationship between folate levels and NTD risk. Resolving the controversy is important in determining public health policy. Methods Data from two studies conducted in Ireland and China were used to determine the relationship between serum folate and NTD risk. The relationship from each study was compared with the observed result in a randomised trial of folic acid that increased serum folate from 5 ng/ml to 44 ng/ml among the women who took the daily folic acid supplement before and during early pregnancy. Results Data from both studies showed a proportional (logarithmic) relationship between serum folate and NTD risk with no evidence of a folate threshold above which there is no further NTD risk reduction. Both studies accurately predicted the observed result from the randomised trial that achieved serum folate levels beyond the average levels found in the general population with an 83% preventive effect. This is higher than can be achieved with current levels of folic acid food fortification or with the recommended peri-conceptional use of 0.4mg supplements. The suggestion of a threshold is not due to discrepant data but the incorrect interpretation of the folate-NTD risk association when plotted on arithmetic scales which conceals the proportional relationship between the two. Conclusion To achieve fully effective fortification serum folate levels need to be about 44ng/ml. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript

The deluge of so-called multiple cancer early detection (MCED) tests has given cause for both excitement and concern. A notable example is the GRAIL-Galleri test1 (Galleri-MCED test), which claims to identify more than 50 different cancers and their location with the use of a blood test that captures circulating tumour DNA linked to aberrant methylation.

Objective To clarify the performance of polygenic risk scores in population screening, individual risk prediction, and population risk stratification.Design Secondary analysis of data in the Polygenic Score Catalog.Setting Polygenic Score Catalog, April 2022. Secondary analysis of 3915 performance metric estimates for 926 polygenic risk scores for 310 diseases to generate estimates of performance in population screening, individual risk, and population risk stratification.Participants Individuals contributing to the published studies in the Polygenic Score Catalog.Main outcome measures Detection rate for a 5% false positive rate (DR5) and the population odds of becoming affected given a positive result; individual odds of becoming affected for a person with a particular polygenic score; and odds of becoming affected for groups of individuals in different portions of a polygenic risk score distribution. Coronary artery disease and breast cancer were used as illustrative examples.Results For performance in population screening, median DR5 for all polygenic risk scores and all diseases studied was 11% (interquartile range 8-18%). Median DR5 was 12% (9-19%) for polygenic risk scores for coronary artery disease and 10% (9-12%) for breast cancer. The population odds of becoming affected given a positive results were 1:8 for coronary artery disease and 1:21 for breast cancer, with background 10 year odds of 1:19 and 1:41, respectively, which are typical for these diseases at age 50. For individual risk prediction, the corresponding 10 year odds of becoming affected for individuals aged 50 with a polygenic risk score at the 2.5th, 25th, 75th, and 97.5th centiles were 1:54, 1:29, 1:15, and 1:8 for coronary artery disease and 1:91, 1:56, 1:34, and 1:21 for breast cancer. In terms of population risk stratification, at age 50, the risk of coronary artery disease was divided into five groups, with 10 year odds of 1:41 and 1:11 for the lowest and highest quintile groups, respectively. The 10 year odds was 1:7 for the upper 2.5% of the polygenic risk score distribution for coronary artery disease, a group that contributed 7% of cases. The corresponding estimates for breast cancer were 1:72 and 1:26 for the lowest and highest quintile groups, and 1:19 for the upper 2.5% of the distribution, which contributed 6% of cases.Conclusion Polygenic risk scores performed poorly in population screening, individual risk prediction, and population risk stratification. Strong claims about the effect of polygenic risk scores on healthcare seem to be disproportionate to their performance.

(1) It is a process of selection with the purpose of identifying those individuals who are at a sufficiently high risk of a specific disorder to warrant further investigation, or sometimes direct preventive action. It is usually a preliminary process to offering a diagnostic test and, if required, preventive action. (2) It is systematically offered to a population who have not sought medical attention on account of symptoms of the disease for which screening is being conducted. It is normally initiated by medical authorities and not by a patient’s request for help on account of a specific complaint. (3) Its purpose is to benefit the individuals being screened. On this basis, mass testing activities such as surveillance for HIV infection or pre-employment examinations to test fitness for work would not be classified as medical screening.

OBJECTIVES:Unconjugated estriol (uE3) is used as a marker for fetal aneuploidy in maternal serum screening tests. The goal of this study was to examine the validity of a new immunoassay for uE3 that uses a monoclonal antibody (m-uE3) rather than the more commonly used polyclonal antibody (p-uE3). SETTING:Assays were performed in the Special Chemistry laboratory at Women and Infants Hospital of Rhode Island. METHODS:Residual fresh (n = 100) and frozen (n = 533) second trimester serum samples from routine clinical care were tested using p-uE3 and/or m-uE3 assays. Assay results were compared between methods using Bland-Altman plots. A median equation was developed for m-uE3 results. Down syndrome risks were compared between the two assays in a case-control sample set (21 cases each matched with five controls for the completed week of gestation, duration of freezer storage and race). RESULTS:Log-transformed serum uE3 levels were highly correlated between the assays (r = 0.93, p < 0.001), with the m-uE3 assay levels yielding, on average, 23% higher (standard deviation of differences in log uE3 concentrations = 0.07) results. Assay and gestation-based median equations were calculated and used to convert m-uE3 concentrations to multiples of the median (MoM). The m-uE3 MoM values fit a log Gaussian distribution well with a log standard deviation of 0.11. Down syndrome risk results were not significantly different between assays. CONCLUSIONS:The m-uE3 assay, with results expressed in MoMs, is suitable for screening and as a monoclonal-based assay offers the advantage of a predictable and indefinite supply of antibody to perform the assay.

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Despite being documented it is not widely recognized that important causal risk factors of potential significance in the primary prevention of disease usually make poor screening tests. This arises because the quantitative association between causal risk factors and disease is usually too small for the risk factor to be a useful screening test. Two examples are the measurement of serum cholesterol as a screening test for heart attacks and blood pressure measurement as a screening test for stroke. While these risk factors are the drivers of heart attacks and strokes throughout the world, when considered as screening tests, they typically have detection rates (sensitivities) for a 5% false positive rate (DR5) of no more than 15% to 20%. Even non-causal risk factors have been invoked as screening tests when their screening performance is poor, for example, coronary calcification as a possible test for coronary heart disease. There is a numerical relationship between measures widely used in investigating causal risk factors such as relative risk or odds ratios and measures of screening performance such as the DR5. A web-based Risk–Screening Converter is available on the Medical Screening Society website (https://www.medicalscreeningsociety.com/rsc.asp). The Risk–Screening Converter converts measures identified as risk factors in epidemiological studies which have a Gaussian distribution into measures of screening performance of potential tests and vice versa. The Converter can be used to determine whether measures such as the odds ratio across the highest and lowest quintile groups of a risk factor are large enough to be considered as a screening test. For example, the Risk–Screening Converter can be used to show that cholesterol is not a good screening test for ischaemic heart disease. In a study of the concentration of total cholesterol in men with a future ischaemic heart disease event the odds ratio between the highest and lowest quintile groups of the distribution of serum total cholesterol was approximately 3.3, similar to the results from other studies. When this odds ratio is entered into the Risk–Screening Converter (see Figure 1) an estimated DR5 of 11.2% is obtained showing that serum cholesterol measurement in adults is not a good screening test for ischaemic heart disease despite it being widely used for this purpose. The Converter has been used in a study to assess the incremental value of polygenic risk scores (PRS) over traditional risk factor scores in the prediction of coronary heart disease events. The study used the results from five cohorts. The cohort with the most discriminatory PRS reported an odds ratio of 4.51 between the highest and lowest quintile groups of the distribution of PRS. The Converter was used in the study to show that this odds ratio corresponds to a false positive rate of 77.1% at a 90% detection rate (FPR90), which is equivalent to a DR5 of 13.5%. The Converter shows that adding a PRS to traditional risk scores adds only a few percentage points to the DR5.

We welcome the findings presented by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC),1Blood Pressure Lowering Treatment Trialists' CollaborationAge-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis.Lancet. 2021; 398: 1053-1064Google Scholar showing that from about the age of 50 years, even people with blood pressure that is so-called normal stand to benefit from preventive medication to lower blood pressure and thereby reduce the risk of cardiovascular disease. These results, however, merely confirm what became known from large systematic reviews and meta-analyses that were done more than a decade ago but not cited by the BPLTTC.2Law MR Wald NJ Morris JK Jordan RE Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials.BMJ. 2003; 326: 1427-1431Google Scholar, 3Law MR Morris JK Wald NJ Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies.BMJ. 2009; 338b1665Google Scholar Similar outcomes have also emerged from a systematic review and meta-analysis of the effects of statins in lowering serum LDL cholesterol concentrations, reducing the incidence of ischaemic heart disease events and stroke.4Law MR Wald NJ Rudnicka AR Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.BMJ. 2003; 326: 1423-1427Google Scholar The blood pressure and cholesterol evidence underpinned the Polypill concept in the primary prevention of cardiovascular diseases.5Wald NJ Law MR A strategy to reduce cardiovascular disease by more than 80%.BMJ. 2003; 326: 1419-1423Google Scholar The BPLTTC's meta-analysis does not close an evidence gap, as the collaborators assert, but highlights an implementation gap, which urgently needs to be closed so that the potential substantial reduction in cardiovascular disease can be realised globally. NJW, ML, DSW, and JKA are founders and joint owners of Polypill, which provides an online preventive medical service. JM declares no competing interests. Blood pressure meta-analysis highlights an implementation gap – Authors’ replyWe thank Nicholas Wald and colleagues for their interest in our work.1 They propose that our findings merely confirmed what has been previously known, as reported by them. Full-Text PDF Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysisPharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines. Full-Text PDF Open Access

Neural tube defects (NTDs) are a group of relatively common fatal or severely disabling birth defects that result in about 300,000 cases a year world-wide. The search for a cause was elusive, but in 1991 it was shown that about 8 out of 10 cases are due to a lack of vitamin B9 (folate) and are therefore preventable. This article (i) describes the challenge in finding the cause; (ii) examines the reasons for the failure of many countries to introduce folic acid fortification of staple foods such as flour and rice; (iii) shows that countries that have introduced fortification failed to do so in a fully effective way; (iv) shows how current preventive polices are confusing, inconsistent and sub-optimal; (v) shows that the proposed UK folic acid fortification policy is expected to prevent about 1 out of 10 NTD cases only; and (vi) proposes a simple, fully effective fortification policy that would prevent about 8 out of 10 NTDs and avoid the need for women to start taking folic acid supplements before pregnancy, a policy that has been shown to fail because only a small percentage of women adopt this practice. Keywords neural tube defects , folic acid , prevention , public health policy