Series in Intensive Medicine: Methodological update in Medicina Intensiva
Frequent methodological errors in clinical research
Errores metodológicos frecuentes en la investigación clínica
L.C. Silva Aycaguer
Escuela Nacional de Salud Pública de Cuba, Ciudad de La Habana, Cuba
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Silva Aycaguer" "autores" => array:1 [ 0 => array:2 [ "nombre" => "L.C." "apellidos" => "Silva Aycaguer" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173572718301905" "doi" => "10.1016/j.medine.2018.10.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572718301905?idApp=WMIE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210569118300123?idApp=WMIE" "url" => "/02105691/0000004200000009/v1_201811220619/S0210569118300123/v1_201811220619/es/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S2173572718302078" "issn" => "21735727" "doi" => "10.1016/j.medine.2018.07.009" "estado" => "S300" "fechaPublicacion" => "2018-12-01" "aid" => "1244" "copyright" => "Elsevier España, S.L.U. and SEMICYUC" "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Intensiva. 2018;42:547-50" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 986 "formatos" => array:3 [ "EPUB" => 141 "HTML" => 532 "PDF" => 313 ] ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Point of view</span>" "titulo" => "Life-support tools for improving performance of the Surviving Sepsis Campaign Hour-1 bundle" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "547" "paginaFinal" => "550" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Herramientas de soporte vital para mejorar la ejecución del paquete de medidas de 1 hora de la <span class="elsevierStyleItalic">Surviving Sepsis Campaign</span>" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2917 "Ancho" => 2314 "Tamanyo" => 694247 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The Rational Life Support in Sepsis (RALSS) algorithm. This algorithm is based on the Surviving Sepsis Campaign (SSC) hour-1 bundle of care, as well as adapted to the institutional protocol and available resources. At time zero, clinician on charge should suggest verbally and share with other staff members the diagnosis (<span class="elsevierStyleItalic">say</span> sepsis), <span class="elsevierStyleItalic">look for</span> the source (and <span class="elsevierStyleItalic">consider</span> imaging studies), <span class="elsevierStyleItalic">attach</span> the monitor to the patient and <span class="elsevierStyleItalic">obtain</span> at least 2 blood and other cultures according to clinical suspicion (preferably before administration of broad-spectrum antibiotics) <span class="elsevierStyleBold">(box 1)</span>. Afterwards, administration of appropriate IV antibiotic(s) and the best strategy for control of sepsis source should be ensured (if a drainable focus of infection is present) <span class="elsevierStyleBold">(box 2)</span>. <span class="elsevierStyleItalic">Sepsis without hypotension</span><span class="elsevierStyleBold">(box 3)</span><span class="elsevierStyleItalic">or Sepsis and hypotension</span><span class="elsevierStyleBold">(box 4)</span> pathway should be followed according to patient status. If hypotension is present, <span class="elsevierStyleItalic">start</span> resuscitation with IV fluids (30<span class="elsevierStyleHsp" style=""></span>ml/kg) and re-measure lactate if initial value was >2<span class="elsevierStyleHsp" style=""></span>mmol/L or if clinical deterioration exists although the initial lactate was ≤2<span class="elsevierStyleHsp" style=""></span>mmol/L <span class="elsevierStyleBold">(box 5)</span>. If hypotension persists and lactate is >2<span class="elsevierStyleHsp" style=""></span>mmol/L start vasopressors <span class="elsevierStyleBold">only</span> in those patients who have received an initial resuscitation with IV fluids and are not considered to be hypovolemic <span class="elsevierStyleBold">(box 6 and box 7)</span>. In septic shock patients assess for fluid responsiveness and ask for an intensivist consultation <span class="elsevierStyleBold">(box 7)</span>. Continuous assessment of clinical and laboratory variables and control of focus of infection reassessment may be carried out to enhance initial resuscitation interventions <span class="elsevierStyleBold">(box 8)</span>. Complementary assessments may be requested, and institutional protocol activated. During all interventions continuous reassessment and ruling out of other sources of shock should be conducted <span class="elsevierStyleBold">(box 9</span>). <span class="elsevierStyleItalic">ID</span> denotes Infectious Diseases, <span class="elsevierStyleItalic">MAP</span> mean arterial pressure, <span class="elsevierStyleItalic">SAP</span> systolic arterial pressure, <span class="elsevierStyleItalic">DAP</span> diastolic arterial pressure, <span class="elsevierStyleItalic">ScVO<span class="elsevierStyleInf">2</span></span> central venous oxygen saturation, <span class="elsevierStyleItalic">PCO<span class="elsevierStyleInf">2</span></span> Partial pressure of carbon dioxide, <span class="elsevierStyleItalic">ICU</span> intensive care unit. <span class="elsevierStyleSup">a</span> Do not significantly delay antimicrobial therapy while awaiting for cultures or blood samples. Out-of-hospital approach should attempt to store baseline blood samples for rapid analysis at hospital admission. <span class="elsevierStyleSup">b</span> Broad-spectrum antibiotics considering the likely etiology of infection, specific drug properties and increased extra-renal drug elimination during sepsis/septic shock, history of multidrug-resistant microorganisms, presence of acute kidney injury (±renal replacement therapies) or liver failure and presence of obesity.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E.P. Plata-Menchaca, R. Ferrer" "autores" => array:2 [ 0 => array:2 [ "nombre" => "E.P." "apellidos" => "Plata-Menchaca" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Ferrer" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572718302078?idApp=WMIE" "url" => "/21735727/0000004200000009/v1_201811250605/S2173572718302078/v1_201811250605/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2173572718301887" "issn" => "21735727" "doi" => "10.1016/j.medine.2018.02.005" "estado" => "S300" "fechaPublicacion" => "2018-12-01" "aid" => "1184" "copyright" => "Elsevier España, S.L.U. and SEMICYUC" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Intensiva. 2018;42:534-40" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 724 "formatos" => array:3 [ "EPUB" => 128 "HTML" => 347 "PDF" => 249 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Pharmacist adscription to intensive care: Generating synergies" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "534" "paginaFinal" => "540" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Adscripción del farmacéutico a cuidados intensivos: generando sinergias" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.T. Franco Sereno, R. Pérez Serrano, R. Ortiz Díaz-Miguel, M.C. Espinosa González, H. Abdel-Hadi Álvarez, A. Ambrós Checa, M. Rodríguez Martínez" "autores" => array:7 [ 0 => array:2 [ "nombre" => "M.T." "apellidos" => "Franco Sereno" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Pérez Serrano" ] 2 => array:2 [ "nombre" => "R." "apellidos" => "Ortiz Díaz-Miguel" ] 3 => array:2 [ "nombre" => "M.C." "apellidos" => "Espinosa González" ] 4 => array:2 [ "nombre" => "H." "apellidos" => "Abdel-Hadi Álvarez" ] 5 => array:2 [ "nombre" => "A." "apellidos" => "Ambrós Checa" ] 6 => array:2 [ "nombre" => "M." "apellidos" => "Rodríguez Martínez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0210569118300524" "doi" => "10.1016/j.medin.2018.02.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210569118300524?idApp=WMIE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572718301887?idApp=WMIE" "url" => "/21735727/0000004200000009/v1_201811250605/S2173572718301887/v1_201811250605/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Series in Intensive Medicine: Methodological update in Medicina Intensiva</span>" "titulo" => "Frequent methodological errors in clinical research" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "541" "paginaFinal" => "546" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "L.C. Silva Aycaguer" "autores" => array:1 [ 0 => array:3 [ "nombre" => "L.C." "apellidos" => "Silva Aycaguer" "email" => array:1 [ 0 => "lcsilva@infomed.sld.cu" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Escuela Nacional de Salud Pública de Cuba, Ciudad de La Habana, Cuba" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Errores metodológicos frecuentes en la investigación clínica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 860 "Ancho" => 1593 "Tamanyo" => 66536 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Evolution of the number of predatory journals between 2011 and 2017.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In the opening years of this century, the epidemiologist and statistician of Greek origin and professor at Stanford University, John Ioannidis, published an article<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a> in which he argued that contemporary research in the field of healthcare mostly comes to wrong conclusions. A claim of this magnitude inevitably stirred the scientific community and generated enormous interest. In effect, as the author himself explains in a brief interview that can be accessed on YouTube (<a id="intr0010" class="elsevierStyleInterRef" href="https://www.youtube.com/watch?v=KOZAV9AvIQE">https://www.youtube.com/watch?v=KOZAV9AvIQE</a>), far over one million people have read the article. In fact, it has been the most frequently consulted publication in the prestigious open access journal <span class="elsevierStyleItalic">PLOS Medicine</span> since its creation in 2004.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Eleven years later, Ioannidis has published a complementary article in the same journal<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">2</span></a> that proves just as disturbing as the first, if not more so. The article, entitled: “Why most clinical research is not useful”, states that “In general, not only are most research findings false, but even worse, most of the findings that are true are not useful”.</p><p id="par0015" class="elsevierStylePara elsevierViewall">There are many causes underlying this problem, though in principle it is obvious that neither authors nor editors wish to make mistakes or engage in futile efforts. This worrisome reality has caused the journal <span class="elsevierStyleSmallCaps">Medicina</span>I<span class="elsevierStyleSmallCaps">ntensiva</span> to promote an analysis of the errors that frequently affect clinical studies or their divulgation. The present contribution seeks to examine some of these errors.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Appropriation of the findings of others, deliberate omissions, or manipulating interpretations cannot be regarded as “errors”. Those are simply examples of misbehavior deserving direct repulsion. Unfortunately, the recent history of clinical research is plagued by behaviors of this kind seeking to ensure that certain procedures receive commercial success even if they are useless, if not directly harmful. The evidence in this respect is abundant and undeniable. Perhaps one of the best exponents of this is the book published by Peter Gøtzsche,<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">3</span></a> director of the <span class="elsevierStyleItalic">Nordic Cochrane Center</span>, entitled “Deadly medicines and organized crime. How big pharma has corrupted health care”, which has recently been published in Spain.</p><p id="par0025" class="elsevierStylePara elsevierViewall">According to PubMed, out of a total of 2047 scientific articles that were disqualified following publication (the so-called “retractions”) over the last four decades, only one-fifth were attributable to errors.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">4</span></a> The rest represented cases of fraud or suspected fraud.</p><p id="par0030" class="elsevierStylePara elsevierViewall">A study published in 2015 and involving 57 controlled clinical trials carried out between 1998 and 2013 reported that the United States Food and Drug Administration (FDA) had discovered that 22 (almost 40%) provided false information; 35 (61%) contained inadequate or inexact registries; one out of every four failed in reporting adverse reactions; three out of every four contained breaches in protocol; and more than 50% did not guarantee adequate patient protection (problems referred to safety or informed consent).<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">5</span></a> The respective publications made no mention of such malpractice, and the truth is that it is difficult to know whether such shortcomings were attributable to deliberate decisions or not.</p><p id="par0035" class="elsevierStylePara elsevierViewall">We understand that when the editors of <span class="elsevierStyleSmallCaps">Medicina</span>I<span class="elsevierStyleSmallCaps">ntensiva</span> decided to dedicate journal space to address commonly made errors, they did not intend to alert to data falsification or plagiarism, but rather aimed to draw attention to those errors that occasionally may result from out of date information or neglect. Still, it must be underscored that the dividing line between error and fraudulent behavior is thin.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In the following lines we will use the term “error” in reference to certain practices that may well carry false intentions, though not necessarily so. In any case, it would be useful for intensivists to avoid blunders that could be regarded as academic fraud, as these may generate doubts that cannot always be unequivocally refuted.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">6</span></a> For this reason, some of the examples which the reader will find in this article may correspond to either misbehavior or to innocent consequences of ignorance or a lack of awareness of the requirements of good research practice.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In any case, this article does not intend to offer an exhaustive inventory of the possible errors. The literature contains a series of such inventories,<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">8–12</span></a> the most exhaustive of which (describing over 50 common errors) has been published by Strasak et al.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">13</span></a> Since these sources can be easily consulted, we will not examine the most repeated errors but rather the least evidenced and most controversial errors – though this does not mean that they are any less frequent. Furthermore, we have decided to address each problem in some detail rather than to examine many problems only superficially.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A description and comment are provided below of 6 errors that meet the aforementioned criteria and which we have chosen in view of their relevance and persistent appearance in publications.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical irrelevance and social irresponsibility</span><p id="par0055" class="elsevierStylePara elsevierViewall">A study<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">14</span></a> based on 704 articles submitted in 2000–2001 to two top level journals (the British Medical Journal and the Annals of Internal Medicine) for possible publication showed that 514 (73%) had received the support of an expert in methodology and statistics. The rejection rate was 71% for those articles that lacked such support versus only 57% for those with such support. These data appear to confirm the advantage of having a statistician among the signing authors. Unfortunately, many health professionals appear to harbor the absurd conviction that any investigator “can” (or even worse “must”) master statistics as if it were a mere question of basic grammar. However, the true mastery of statistical techniques requires highly specialized knowledge. This may explain a widespread practice in this field that deserves special mention: the wrong use of statistical significance tests (SSTs).<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The “<span class="elsevierStyleItalic">p</span>-value” criteria are varied and diverse, and many studies have been dedicated to establish them. Decades ago, the International Committee of Medical Journal Editors<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">16</span></a> explicitly rejected the use of “<span class="elsevierStyleItalic">p</span>-values” neglecting the estimation of effects. In order to gain a more in-depth perspective of the highly negative consequences of not paying attention to this recommendation, mention should be made of the current declarations of 72 outstanding investigators in different fields,<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">17</span></a> as well as of a recent detailed analysis on the subject.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">We will focus on the most serious consequence of the non-critical and unwarranted use of SSTs: the generalized and systematic attribution of clinical (or public health) importance to therapeutic or preventive procedures that are actually very far from having any such importance.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Imagine that we are comparing recovery rates referred to a given disease following the administration of two treatments (e.g., conventional treatment versus novel therapy), and that on applying a hypothesis test we obtain a “<span class="elsevierStyleItalic">p</span>-value” of under 0.05. What we could affirm is that there is sound evidence for considering that the two treatments are not equal. No more no less. However, there is a generalized habit of interpreting this result as meaning that “the difference between the treatments is significant”. This actually constitutes a misuse of language, since we are implicitly suggesting that “the difference is relevant or substantial”.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In order to confirm that this is no mere problem of semantics, and to illustrate the incapacity of “<span class="elsevierStyleItalic">p</span>-values” to convert trivial effects into sound generic recommendations, we will examine a particularly expressive example in the form of a clinical trial published in <span class="elsevierStyleItalic">The Lancet</span> on the preventive usefulness of two platelet inhibitors: Plavix<span class="elsevierStyleSup">®</span> (clopidogrel) and Aspirin<span class="elsevierStyleSup">®</span> (acetylsalicylic acid).<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">19</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The mentioned study “demonstrates” that Plavix<span class="elsevierStyleSup">®</span> (marketed by Sanofi, the company that sponsored the trial) is more effective than Aspirin<span class="elsevierStyleSup">®</span> in reducing serious vascular events in patients at a high risk of suffering such events.</p><p id="par0085" class="elsevierStylePara elsevierViewall">The study population consisted of patients with a recent history of myocardial infarction (occurring within the previous 35 days), or with a history of ischemic stroke in the 6 preceding months. Following randomized allotment, the two treatments were administered to about 20,000 individuals meeting the aforementioned criteria. The study endpoint was the occurrence of repeat ischemic stroke or myocardial infarction (whether fatal or otherwise), or any death of vascular origin.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The megastudy estimated a risk of D1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>583 events per 10,000 subjects-year of treatment with Aspirin<span class="elsevierStyleSup">®</span> and D2<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>532 events per 10,000 subjects-year of treatment with Plavix<span class="elsevierStyleSup">®</span>. After applying an SST, the study triumphantly registered <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.043 and concluded that Plavix<span class="elsevierStyleSup">®</span> has greater preventive capacity than Aspirin<span class="elsevierStyleSup">®</span>.</p><p id="par0095" class="elsevierStylePara elsevierViewall">It is obvious that the overall high risk patients would spare themselves a mere D1<span class="elsevierStyleHsp" style=""></span>−<span class="elsevierStyleHsp" style=""></span>D2<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>51 events per 10,000 subjects-year of preventive treatment when using Plavix<span class="elsevierStyleSup">®</span> instead of Aspirin<span class="elsevierStyleSup">®</span>.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Consequently, a rational decision-maker in principle would refrain from recommending Plavix<span class="elsevierStyleSup">®</span> (a much more expensive drug). However, even if the mentioned difference were considered “important”, it clearly would make no sense at all to cite the <span class="elsevierStyleItalic">p</span>-value in the recommendation made. Any decision can (and must) be based on the D1 and D2 values, accompanied by other information such as the cost and adverse effects. The only role of the <span class="elsevierStyleItalic">p</span>-value in the article (and subsequently in its many citations) is to provide coverage for those who manufacture Plavix<span class="elsevierStyleSup">®</span>, taking advantage of the non-critical use of the statistics and SST, along with the error (or trick<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">20</span></a>) of omitting the true significance in practical terms of the product they are recommending.</p><p id="par0105" class="elsevierStylePara elsevierViewall">This is no isolated example. The SST “dictatorship” is still fully present in the biomedical literature. The Finnish professor Esa Läärä wrote: “The reporting of trivial and meaningless “results” that do not afford adequate quantitative information of scientific interest is a very widespread practice”.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">21</span></a> A couple of examples suffice to confirm this. An analysis of 71 anticancer drugs consecutively approved for the treatment of solid tumors between 2002 and 2012<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">22</span></a> found the overall survival and disease-free interval of the drugs to be 2.1 and 2.3 months, respectively.</p><p id="par0110" class="elsevierStylePara elsevierViewall">The standards of the American Society of Clinical Oncology for considering that a drug offers “significant clinical benefit” are clearly not related to “statistical significance”. Between April 2014 and February 2016, the Food and Drug Administration approved 46 antineoplastic drugs. A recent article published in a specialized journal<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">23</span></a> showed that only 9 (19%) met these standards.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Unacceptable generalizations</span><p id="par0115" class="elsevierStylePara elsevierViewall">The results of a clinical trial cannot be abruptly applied to individuals that fall outside the context of the sample on which the trial is based. All studies must have a series of inclusion criteria (those specifying which subjects can be incorporated to the sample representing the study population) and exclusion criteria (those specifying the characteristics of the subjects that cannot be incorporated to the sample). For example, it may be established that a study will include non-asthmatic adults and cannot include pregnant women. If the study drug proves successful after one month of treatment of a certain illness, it should not be recommended in pregnant women or asthmatic individuals, and the drug should not be used for any period of time other than one month (no longer, no shorter).</p><p id="par0120" class="elsevierStylePara elsevierViewall">Obviously, the way in which a given outcome is applied is not the responsibility of those who obtained the outcome. However, it is not infrequent to make the mistake of not reporting such restrictions in the abstract and conclusions of an article. Furthermore, since these are the sections of the publication that are usually read most carefully, there is an implicit invitation for the reader to apply the results or outcomes beyond what is actually permissible.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Selection bias: the Vioxx<span class="elsevierStyleSup">®</span> tragedy</span><p id="par0125" class="elsevierStylePara elsevierViewall">Rofecoxib, a powerful analgesic marketed by Merck under the brand name Vioxx<span class="elsevierStyleSup">®</span> and used by about 84 million people worldwide, appeared on the market in 1999 in over 80 countries. It was used to treat the symptoms of osteoarthritis and rheumatoid arthritis, acute pain and menstrual pain. In the year 2000, The New England Journal of Medicine reported on the VIGOR study, involving 8076 patients, of which one-half (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4029) were randomized to 500<span class="elsevierStyleHsp" style=""></span>mg of naproxen (an old nonsteroidal anti-inflammatory drug) twice a day, while the rest (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4074) received 50<span class="elsevierStyleHsp" style=""></span>mg of rofecoxib once a day.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">24</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The endpoint was any gastrointestinal adverse effect, precisely because the purported advantage of the new drug was that it allowed the treatment of pain in chronic disorders without causing symptomatic gastric ulcers or gastrointestinal bleeding – these being undesirable effects typical of the classical analgesics. The results were strongly favorable to Vioxx<span class="elsevierStyleSup">®</span>.</p><p id="par0135" class="elsevierStylePara elsevierViewall">As became known much later, the Vice-Chairperson of clinical research at Merck, and a signing author of the mentioned study, had proposed in 1997, in an internal document of the company, that the intended clinical trial should exclude people with prior cardiovascular problems, “to ensure that the differences in complications between those receiving Vioxx<span class="elsevierStyleSup">®</span> and those receiving a classical analgesic would not be evident”. In other words, Merck was not only already aware of the possible cardiac toxicity of the new drug but also planned selection bias in order to prevent such complications from appearing during the trial.</p><p id="par0140" class="elsevierStylePara elsevierViewall">In an interview by a British newspaper,<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">25</span></a> David Gram, an investigator of the Food and Drug Administration, the lethal influence in terms of heart attacks caused “the greatest drug-related catastrophe in the history of Medicine: between 89,000 and 139,000 American patients could have died or suffered cardiac disorders as a consequence of the drug”. In view of this situation, on 30 September 2004, Merck announced the withdrawal of its drug from the world market.</p><p id="par0145" class="elsevierStylePara elsevierViewall">In this painful yet instructive episode, the company planned and introduced selection bias (one of the incidents related to Vioxx<span class="elsevierStyleSup">®</span> and for which Merck subsequently faced a very heavy fine). However, what should be underscored here is that when such bias is made (even inadvertently), the error can have very serious consequences.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Myths and mistakes referred to required sample size</span><p id="par0150" class="elsevierStylePara elsevierViewall">It is essential to understand something which is usually forgotten by those who theorize about sample size and stick to orthodox and often schematic and ritual positions.<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">26,27</span></a> Ultimately, and practically regardless of the sample size, a study can be potentially useful. The information available for precisely determining a correct sample size (an inherently polemical term) is often inexistent or falls short of the required information, and in any case it is inexorably conditioned by speculation inherent to the choice of data to be used in the calculation.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">28</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">In some cases the sample size is stated to be “insufficient”. This evaluating criterion remains strongly implanted in Ethics Committees, research project evaluating agencies, and editors of scientific journals. However, the legitimacy of such statements is very questionable, since they are conflictive and non-pertinent for at least two reasons.</p><p id="par0160" class="elsevierStylePara elsevierViewall">Firstly, because the formulas used to determine sample size are intrinsically speculative and inevitably imply subjectiveness.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">29</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Secondly, because the term “sufficiently large sample” would only make sense if operative standards or firm conclusions could be drawn from each individual study. However, this delusion is as ingrained as it is incorrect, due to the simple reason that science does not work that way.<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">30,31</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Our scientific convictions may be more or less firm, but they are always provisional, and while our representations of reality may have a degree of credibility at a given point in time, they are open to changes and improvement as new data emerge. The consolidation of new knowledge is gradual, and all contributions are welcome. Some contributions will be more relevant and others less so, but they all add something to the process, independently of the sample size, and generally through the conduction of meta-analyses.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">32</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Clinical research errors are not only made by those who perform the research, but also by those who disclose the results. As an example, in our opinion it is a mistake to demand authors to include the formulas used, and in general to explain their sample sizes. What authors usually do in the face of such demands is what an important article published in The Lancet<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">33</span></a> called “retrofitting” (i.e., choosing values that lead to a sample size that has already been chosen beforehand), and which results in a certain lack of integrity on the part of the authors. The problem is controversial, since the idea that it is necessary to explain the sample size is very ingrained, even though irrational.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">The “negative studies” iceberg</span><p id="par0180" class="elsevierStylePara elsevierViewall">A curious journal called Negative Results<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">35</span></a> has recently been created with the aim of publishing articles that refute or challenge knowledge taken to be true. The initiative is a reaction against the stigma associated with so-called “negative findings”.</p><p id="par0185" class="elsevierStylePara elsevierViewall">So-called “publication bias”, a term first used around 1980,<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">36</span></a> is the tendency to favor the publication of certain articles conditioned to the results they obtain and not necessarily to their merits. The basic reason for this is the reluctance of many editors of medical journals to publish things that make no “novel” contribution, as if the rebuttal of a wrong conviction were not “novel”.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Since then there has been growing awareness of the problem, known as the “file drawer problem”<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">37</span></a>: journals publish a small fraction of the studies that are made (whether useful or not), while most of the remaining studies (those with negative results, i.e., studies failing to yield <span class="elsevierStyleItalic">significance</span>) are confined to the laboratory drawers. As commented in the presentation of the aforementioned journal: “scientific findings are like an iceberg, with the 10% of published findings floating on the 90% of studies with negative results”.</p><p id="par0195" class="elsevierStylePara elsevierViewall">The most serious problem associated with this type of bias, denounced time and time again,<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a> is that it distorts the view we have of reality and therefore compromises the capacity to make correct decisions. Each study may be objective, but our global view no longer remains objective if part of the evidence is suppressed. Naturally, one of the areas most seriously limited by this problem is meta-analysis, the declared purpose of which is to formalize the identification of consensus. Perhaps the most spectacular example in recent times is that of the management of the influenza A pandemic of 2009. As reported in an excellent study that details this episode,<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">39</span></a> in response to the threat, the use of two antiviral agents, Tamiflu<span class="elsevierStyleSup">®</span> (oseltamivir) and Relenza<span class="elsevierStyleSup">®</span> (zanamivir), was recommended. Many governments spent millions of euros on these products.</p><p id="par0200" class="elsevierStylePara elsevierViewall">The decision was warranted by a review of antiviral drugs carried out in 2006 and fundamentally based on a study from 2003, grouping 10 studies (all financed by Roche, the company that markets Tamiflu<span class="elsevierStyleSup">®</span>), and which <span class="elsevierStyleItalic">demonstrated</span> their effectiveness and safety.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">40</span></a> However, many doubts were raised regarding these supposed properties, and scientific and political pressure finally forced the drug companies to share the raw data corresponding to the clinical trials with antivirals, which had been kept under key until then with the argument that they formed part of commercial secrecy. First Glaxo (in relation to Relenza<span class="elsevierStyleSup">®</span>) and a few months later Roche (Tamiflu<span class="elsevierStyleSup">®</span>) submitted the mentioned data to the authors of a new review in 2013. The enormous task of examining about 160,000 pages led to the conclusion that antiviral agents in fact have very modest efficacy in alleviating the symptoms, and no impact in terms of a decrease in complications or deaths. Furthermore, such drugs were seen to produce important adverse effects and proved unable to modify the mechanisms of contagion.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">41</span></a> Likewise, it was found that many negative results had been concealed, the disclosure of desired findings was favored, and negative results were hidden – thereby leading to biased conclusions from the start.</p><p id="par0205" class="elsevierStylePara elsevierViewall">In relation to the problem of suppressing negative results, we firmly believe our readers will enjoy the conference given by Dr. Ben Goldacre, an investigator at the London School of Hygiene and Tropical Medicine, which can be accessed on YouTube (<a id="intr0015" class="elsevierStyleInterRef" href="http://www.ted.com/talks/ben_goldacre_battling_bad_science?language=en">http://www.ted.com/talks/ben_goldacre_battling_bad_science?language=en</a>), in view of its clearness and amenity.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Predatory editorial practices</span><p id="par0210" class="elsevierStylePara elsevierViewall">As investigators, we routinely receive invitations to submit articles to certain journals that are presumably very interested in our scientific contributions. These are very often so-called “predatory journals”: a lucrative and fraudulent phenomenon characterized by features such as promising the rapid publication of articles, the offering of tempting prices, commitment to ensure strict peer reviews which in fact never occur or are extremely weak, the self-attribution of false impact factors, or the inclusion of inexistent academicians on their editorial boards.</p><p id="par0215" class="elsevierStylePara elsevierViewall">In this regard, mention must be made of the work of Jeffrey Beall, a librarian at the University of Colorado, who is famous for having coined the abovementioned term and for having published lists of “potential, possible or probable predatory open access journals and printing houses” in the past. Curiously, in January 2017 Beall canceled the website where he regularly updated his lists.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">42</span></a> His only explanation was that he had been threatened. However, a team that preserves its anonymity, precisely in order to avoid such problems, has continued his task, and keeps the list up to date (<a id="intr0020" class="elsevierStyleInterRef" href="https://predatoryjournals.com/">https://predatoryjournals.com/</a>) for consultation by anyone who wishes to do so.</p><p id="par0220" class="elsevierStylePara elsevierViewall">An idea of the magnitude of the phenomenon can be gained from the trend in number of new journals of this kind since their first appearance in 2011: from 18 journals that year to 23 one year later, and since then the rise has been exponential, reaching 1319 journals in October 2017 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0225" class="elsevierStylePara elsevierViewall">The great volume of polluted information this academic plague generates is evident. However, the reason for mentioning it here is that we consider it a mistake (and not a minor one at that) to submit articles to journals of this kind. Doing so not only contributes to further false editorial practices but also has an impact upon the personal prestige of those who are foolishly trapped by such journals.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">43</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusions</span><p id="par0230" class="elsevierStylePara elsevierViewall">There are many and diverse possible methodological errors in clinical research. Our study examines a small group of them in the hope of alerting intensivists to mistakes that are not always repaired. Improper statistical processing, the omission of crucial elements, inertial behaviors and the lack of criterion in publishing have been described using examples. While not always intentional, such errors are equally damaging to medical science, which has been experiencing moments of crisis ever since John Ioannidis shook the scientific community with his penetrating contributions cited at the start of this paper.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of interest</span><p id="par0235" class="elsevierStylePara elsevierViewall">The author declares that he has no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1113337" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1051127" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1113338" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1051126" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical irrelevance and social irresponsibility" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Unacceptable generalizations" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Selection bias: the Vioxx tragedy" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Myths and mistakes referred to required sample size" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "The “negative studies” iceberg" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Predatory editorial practices" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conclusions" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-11-02" "fechaAceptado" => "2017-12-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1051127" "palabras" => array:6 [ 0 => "Clinical trials" 1 => "Statistical significance tests" 2 => "Fraud" 3 => "Selection bias" 4 => "Sample size" 5 => "Predatory journals" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1051126" "palabras" => array:6 [ 0 => "Ensayos clínicos" 1 => "Pruebas de significación estadística" 2 => "Fraude" 3 => "Sesgo de selección" 4 => "Tamaño muestral" 5 => "Revistas depredadoras" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Several errors that are frequently present in clinical research are listed, discussed and illustrated. A distinction is made between what can be considered an “error” arising from ignorance or neglect, from what stems from a lack of integrity of researchers, although it is recognized and documented that it is not easy to establish when we are in a case and when in another. The work does not intend to make an exhaustive inventory of such problems, but focuses on those that, while frequent, are usually less evident or less marked in the various lists that have been published with this type of problems. It has been a decision to develop in detail the examples that illustrate the problems identified, instead of making a list of errors accompanied by an epidermal description of their characteristics.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se enumeran, discuten e ilustran diversos errores que se presentan con frecuencia en la investigación clínica. Se hace una distinción entre lo que puede considerarse un «error» surgido de la ignorancia o el descuido, de aquello que dimana de una falta de integridad de los investigadores, aunque se reconoce y documenta que no es fácil establecer cuándo estamos en un caso y cuándo en otro. El trabajo no se propone hacer un inventario exhaustivo de tales pifias, sino que se concentra en aquellas que, sin dejar de ser frecuentes, suelen ser menos evidentes o menos señaladas en los diversos listados que se han publicado con este tipo de problemas. Se ha optado por desarrollar en detalle los ejemplos que ilustran los problemas señalados en lugar de hacer una relación de errores acompañados de una descripción epidérmica de sus características.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Silva Aycaguer LC. Errores metodológicos frecuentes en la investigación clínica. Med Intensiva. 2018;42:541–546.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 860 "Ancho" => 1593 "Tamanyo" => 66536 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Evolution of the number of predatory journals between 2011 and 2017.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0220" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Why most published research findings are false" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.P.A. Ioannidis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pmed.0020124" "Revista" => array:5 [ "tituloSerie" => "PLoS Med" "fecha" => "2005" "volumen" => "2" "paginaInicial" => "e124" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16060722" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0225" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Why most clinical research is not useful" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.P.A. Ioannidis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pmed.1002049" "Revista" => array:5 [ "tituloSerie" => "PLoS Med" "fecha" => "2005" "volumen" => "13" "paginaInicial" => "e1002049" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27328301" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0230" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deadly medicines and organized crime. How big pharma has corrupted health care" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P.C. Gøtzsche" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2013" "editorial" => "Radcliffe Publishing Ltd." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 15 | 10 | 25 |
| 2024 October | 87 | 51 | 138 |
| 2024 September | 89 | 42 | 131 |
| 2024 August | 88 | 53 | 141 |
| 2024 July | 99 | 30 | 129 |
| 2024 June | 95 | 50 | 145 |
| 2024 May | 80 | 36 | 116 |
| 2024 April | 78 | 36 | 114 |
| 2024 March | 109 | 31 | 140 |
| 2024 February | 77 | 47 | 124 |
| 2024 January | 92 | 36 | 128 |
| 2023 December | 93 | 35 | 128 |
| 2023 November | 102 | 42 | 144 |
| 2023 October | 94 | 30 | 124 |
| 2023 September | 76 | 34 | 110 |
| 2023 August | 58 | 18 | 76 |
| 2023 July | 93 | 29 | 122 |
| 2023 June | 97 | 25 | 122 |
| 2023 May | 139 | 45 | 184 |
| 2023 April | 111 | 32 | 143 |
| 2023 March | 184 | 45 | 229 |
| 2023 February | 134 | 36 | 170 |
| 2023 January | 117 | 20 | 137 |
| 2022 December | 136 | 40 | 176 |
| 2022 November | 154 | 49 | 203 |
| 2022 October | 179 | 35 | 214 |
| 2022 September | 96 | 24 | 120 |
| 2022 August | 130 | 41 | 171 |
| 2022 July | 94 | 37 | 131 |
| 2022 June | 91 | 28 | 119 |
| 2022 May | 126 | 40 | 166 |
| 2022 April | 153 | 52 | 205 |
| 2022 March | 181 | 56 | 237 |
| 2022 February | 118 | 36 | 154 |
| 2022 January | 159 | 35 | 194 |
| 2021 December | 144 | 72 | 216 |
| 2021 November | 167 | 56 | 223 |
| 2021 October | 213 | 98 | 311 |
| 2021 September | 368 | 51 | 419 |
| 2021 August | 182 | 45 | 227 |
| 2021 July | 107 | 38 | 145 |
| 2021 June | 101 | 51 | 152 |
| 2021 May | 132 | 63 | 195 |
| 2021 April | 487 | 105 | 592 |
| 2021 March | 200 | 57 | 257 |
| 2021 February | 157 | 49 | 206 |
| 2021 January | 152 | 26 | 178 |
| 2020 December | 167 | 28 | 195 |
| 2020 November | 176 | 32 | 208 |
| 2020 October | 157 | 43 | 200 |
| 2020 September | 160 | 22 | 182 |
| 2020 August | 119 | 24 | 143 |
| 2020 July | 89 | 41 | 130 |
| 2020 June | 134 | 35 | 169 |
| 2020 May | 160 | 43 | 203 |
| 2020 April | 196 | 47 | 243 |
| 2020 March | 90 | 26 | 116 |
| 2020 February | 245 | 59 | 304 |
| 2020 January | 118 | 38 | 156 |
| 2019 December | 96 | 32 | 128 |
| 2019 November | 165 | 38 | 203 |
| 2019 October | 215 | 30 | 245 |
| 2019 September | 94 | 36 | 130 |
| 2019 August | 80 | 29 | 109 |
| 2019 July | 70 | 18 | 88 |
| 2019 June | 48 | 13 | 61 |
| 2019 May | 74 | 40 | 114 |
| 2019 April | 40 | 21 | 61 |
| 2019 March | 1 | 19 | 20 |
| 2019 February | 0 | 10 | 10 |
| 2019 January | 2 | 7 | 9 |
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