True False Negatives Research Articles

No evidence of false-negative Plasmodium falciparum rapid diagnostic results in Monrovia, Liberia

BackgroundMalaria diagnosis in many malaria-endemic countries relies mainly on the use of rapid diagnostic tests (RDTs). The majority of commercial RDTs used in Africa detect the Plasmodium falciparum histidine-rich protein 2 (PfHRP2). pfhrp2/3 gene deletions can therefore lead to false-negative RDT results. This study aimed to evaluate the frequency of PCR-confirmed, false-negative P. falciparum RDT results in Monrovia, Liberia.MethodsPfHRP2-based RDT (Paracheck Pf®) and microscopy results from 1038 individuals with fever or history of fever (n = 951) and pregnant women at first antenatal care (ANC) visit (n = 87) enrolled in the Saint Joseph’s Catholic Hospital (Monrovia) from March to July 2019 were used to assess the frequency of false-negative RDT results. True–false negatives were confirmed by detecting the presence of P. falciparum DNA by quantitative PCR in samples from individuals with discrepant RDT and microscopy results. Samples that were positive by 18S rRNA qPCR but negative by PfHRP2-RDT were subjected to multiplex qPCR assay for detection of pfhrp2 and pfhrp3.ResultsOne-hundred and eighty-six (19.6%) and 200 (21.0%) of the 951 febrile participants had a P. falciparum-positive result by RDT and microscopy, respectively. Positivity rate increased with age and the reporting of joint pain, chills and shivers, vomiting and weakness, and decreased with the presence of coughs and nausea. The positivity rate at first ANC visit was 5.7% (n = 5) and 8% (n = 7) by RDT and microscopy, respectively. Out of 207 Plasmodium infections detected by microscopy, 22 (11%) were negative by RDT. qPCR confirmed absence of P. falciparum DNA in the 16 RDT-negative but microscopy-positive samples which were available for molecular testing. Among the 14 samples that were positive by qPCR but negative by RDT and microscopy, 3 only amplified pfldh, and among these 3 all were positive for pfhrp2 and pfhrp3.ConclusionThere is no qPCR-confirmed evidence of false-negative RDT results due to pfhrp2/pfhrp3 deletions in this study conducted in Monrovia (Liberia). This indicates that these deletions are not expected to affect the performance of PfHRP2-based RDTs for the diagnosis of malaria in Liberia. Nevertheless, active surveillance for the emergence of PfHRP2 deletions is required.

Which clinical, radiological, histological, and molecular parameters are associated with the absence of enhancement of known breast cancers with Contrast Enhanced Digital Mammography (CEDM)?

BackgroundCEDM has demonstrated a diagnostic performance similar to MRI and could have similar limitations in breast cancer (BC) detection. PurposeThe aim of our study was to systematically analyze the characteristics of the lesions with the absence of enhancement with CEDMs, called false-negatives (FNs), in order to identify which clinical, radiological, histological and molecular parameters are associated with the absence of enhancement of known BCs with CEDMs, and which types of BC are most likely to cause FNs in CEDMs. We also tried to evaluate which parameters instead increased the probability of showing enhancement in the same context. Materials and methodsIncluded in our study group were 348 women with 348 diagnosed BCs performing CEDM as preoperative staging. Two breast-imaging radiologists reviewed the CEDM exams. The absence of perceptible contrast enhancement at the index cancer site was indicative of an FN CEDM, whereas cases with appreciable enhancement were considered true positives (TPs). Dichotomic variables were analyzed with Fisher’s exact probability test or, when applicable, the chi-square test. Binary logistic regression was performed on variables shown to be significant by the univariate analysis in order to assess the relationship between predictors (independent variables) and TFNs (outcome). ResultsEnhancement was observed in 317 (91.1%) of the 348 BCs. From the 31 (8.9%) lesions which were FNs, we excluded 12 (38.7%) which showed an artifact generated by the post biopsy hematoma and 6 (19.4%) which were outside the CEDM field of vision. We thus obtained 13 (41.9%) BCs considered “True False Negatives” (TFNs), i.e. BCs which showed no enhancement despite being within the CEDM field of vision and failed to show post biopsy hematoma artifacts. We found that the TFNs frequently have a unifocal disease extension, diameter <10 mm, a lower number of luminal B HER2-subtypes, a higher number of DCIS, and an index lesion with microcalcifications. ConclusionsThe parameters we found to be associated with no enhancement of known BCs with CEDMs were: unifocal disease extension, DCIS histotype, lesion dimensions <10 mm, and index lesion with microcalcifications. The characteristics that instead increase the probability of showing enhancement were US mass, Luminal B HER2 negative molecular subtype, the presence of an invasive ductal component, and lesion dimensions ≥10 mm.

Characterization of invisible breast cancers in digital mammography and tomosynthesis: Radio-pathological correlation

ObjectiveTo review the radio-pathologic features of symptomatic breast cancers not detected at digital mammography (DM) and digital breast tomosynthesis (DBT). Material and methodsRetrospective analysis of 169 lesions from symptomatic patients with breast cancer that were studied with DM, DBT, ultrasound (US) and magnetic resonance (MR). We identified occult lesions (true false negatives) in DM and DBT. Clinical data, density, US and MR findings were analyzed as well as histopathological results. ResultsWe identified seven occult lesions in DM and DBT. 57 per cent (4/7) of the lesions were identified in high-density breasts (type c and d), and the rest of them in breasts of density type b. Six carcinomas were identified at US and MR (BI-RADS 4 masses); the remaining lesion was only identified at MR. The tumor size was larger than 3cm at MRI in 57 per cent of the lesions. All tumors were ductal infiltrating carcinomas, six of them with high stromal proportion. According to molecular classification, we found only one triple-negative breast cancer, the other lesions were luminal-type. We analyzed the tumor margins of two resected carcinomas that were not treated with neoadjuvant chemotherapy, both lesions presented margins that displaced the adjacent parenchyma without infiltrating it. ConclusionOccult breast carcinomas in DM and DBT accounted for 4 per cent of lesions detected in patients with symptoms. They were mostly masses, all of them presented the diagnosis of infiltrating ductal carcinoma (with predominance of the luminal immunophenotype) and were detected in breasts of density type b, c and d.

Caracterización de cánceres de mama sintomáticos invisibles en mamografía digital y tomosíntesis: correlación radiopatológica

ObjectiveTo review the radio-pathologic features of symptomatic breast cancers not detected at digital mammography (DM) and digital breast tomosynthesis (DBT). Material and methodsRetrospective analysis of 169 lesions from symptomatic patients with breast cancer that were studied with DM, DBT, ultrasound (US) and magnetic resonance (MR). We identified occult lesions (true false negatives) in DM and DBT. Clinical data, density, US and MR findings were analyzed as well as histopathological results. ResultsWe identified seven occult lesions in DM and DBT. 57% (4/7) of the lesions were identified in high-density breasts (type c and d), and the rest of them in breasts of density type b. Six carcinomas were identified at US and MR (BI-RADS 4 masses); the remaining lesion was only identified at MR. The tumor size was larger than 3cm at MRI in 57% of the lesions. All tumors were ductal infiltrating carcinomas, six of them with high stromal proportion. According to molecular classification, we found only one triple-negative breast cancer, the other lesions were luminal-type. We analyzed the tumor margins of two resected carcinomas that were not treated with neoadjuvant chemotherapy, both lesions presented margins that displaced the adjacent parenchyma without infiltrating it. ConclusionOccult breast carcinomas in DM and DBT accounted for 4% of lesions detected in patients with symptoms. They were mostly masses, all of them presented the diagnosis of infiltrating ductal carcinoma (with predominance of the luminal immunophenotype) and were detected in breasts of density type b, c and d.

Factors contributing to false‐negative and potential false‐negative cytology reports in SurePath™ liquid‐based cervical cytology

The characteristics of false-negative conventional cervical cytology smears have been well documented, but there is limited literature available for liquid-based cytology (LBC), especially SurePath™ samples. We aimed to assess the characteristics of false-negative SurePath LBC samples. Over a period of 5 years, an audit of false-negative reports in SurePath cervical cytology was undertaken. In a workload of 183, 112 samples, 481 (0.3%) false negatives were identified using two routes: those detected by routine laboratory internal quality control (rapid pre-screening) (n = 463) and those reported as normal (true false negatives) with concurrent high-grade cervical histology (n = 18). Ninety-five false-negative cases with a subsequent biopsy reported as at least cervical intraepithelial neoplasia grade 2 (CIN2+) were reviewed for a number of different cytomorphological features. Of 95 samples with subsequent CIN2+, 30.5% predominately contained microbiopsies/hyperchromatic crowded cell groups (HCGs), 27.3% sparse dyskarytotic cells, 4.2% pale cell dyskaryosis, 6.3% small dyskaryotic cells; 3.2% were misinterpreted cells, 8.4% contained other distracting cells, 7.4% were low contrast, 5.3% were unexplained and 7.4% were true negatives. The mean number of microbiopsies/HCGs in that category was 4.6. The mean number of abnormal cells in the sparse dyskaryotic cell category was 13.8. Microbiopsies/HCGs were the commonest reason for false negatives. They were usually present in sufficient numbers to be detected but interpretation could be problematic. Dispersed single abnormal cells were usually not identified because of their scarcity or the presence of distracters.

Intra-operative touch preparation cytology following lumpectomy for breast cancer: A series of 400 procedures

Aims Achieving negative margins is essential in conservative treatment for breast cancer. The conventional method for intra-operative assessment of resection margins is gross or histological examination of frozen sections. We describe and evaluate the contribution of an original intra-operative touch preparation cytology (IOTPC) technique (400 procedures) performed on 396 patients. Materials and methods IOTPC consists of touching glass slides to the surfaces of interest after gently pressing the spatially localized specimen taken according to predetermined conditions. The result is conveyed to the surgeon immediately and compared with the conventional histological findings after embedding in paraffin. Results The average response time is 10 min, which renders the technique compatible with standard operating room procedures and its cost is reasonable. The method has a sensitivity of 88.6%, specificity of 92.2%, positive predictive value of 73.6%, negative predictive value of 97%, and correlation with paraffin section histology of 91.5%. Only 5 true false negatives were found in this series and the technique prevented 11.75% of secondary re-excision procedures for positive margins. Conclusion IOTPC is a reliable extemporaneous method for assessing surgical margins in conservative treatment for breast cancer and a useful tool for surgeons.

Reliability of impression cytology for the diagnosis of ocular surface squamous neoplasia employing the Biopore membrane

AIMTo evaluate the accuracy of impression cytology employing a Biopore membrane device in the diagnosis of ocular surface squamous neoplasia (OSSN).METHODSThe histology of patients undergoing excision biopsy for the suspected...

Diagnosis of depression by primary care physicians versus a structured diagnostic interview: Understanding discordance

In this paper, false-negative and false-positive cases of depressive illness are examined, differentiating levels of disagreement between a primary care physician’s diagnosis and a standardized research diagnosis. Two stratified random samples of primary care patients in Seattle, USA ( N = 373) and Groningen, The Netherlands ( N = 340) were examined with the Composite International Diagnostic Interview-Primary Health Care Version (CIDI-PHC). Physician’s severity ratings and diagnosis of psychological disorder were obtained. Three levels of disagreement between physician and CIDI diagnosis were distinguished: 1) complete disagreement about the presence of psychiatric symptoms (true false-negative and true false-positive patients); 2) disagreement over severity of recognized psychological illness (underestimated or overestimated); and 3) disagreement over the specific psychiatric diagnosis among those given a diagnosis (misdiagnosed or given another CIDI diagnosis). All three levels of disagreement were common. Only 27% of the false-negative cases were due to complete disagreement (true false-negatives), and 55% of the false-positives were due to complete disagreement (true false-positives). The true false-negative patients were younger, more often employed, rated their own health more favorably, visited their doctor for a somatic complaint and made fewer visits than the underestimated, misdiagnosed, and concordant positive patients. Complete disagreement in depressive diagnoses between the primary care physician and research interview is not as frequent as indicated by an undifferentiated false-negative/false-positive analysis. Differentiating levels of disagreement does more justice to diagnostic practice in primary care and provides guidance on how to improve the diagnostic accuracy of primary care physicians.

100% Rapid (Partial) Rescreening for Quality Assurance

To compare the efficiency of two methods for routine quality assurance in gynecologic cytology: random rescreening of 10% of negative gynecologic smears and rapid rescreening of all negative gynecologic smears. All gynecologic smears considered to be negative or benign and diagnosed between November 1, 1996, and December 31, 1997, were rescreened using the rapid, partial rescreening technique. Results were compared to those of the 10% random rescreening method. Comparing the 10% review of negatives to the rapid rescreening in two comparable periods of three months, the former required review by the supervisor of 160 cases in order to find a true false negative. With rapid rescreening, the supervisor had to review fewer than eight cases to find a true false negative. Also, rapid rescreening found about four times more true false negatives than random 10% review. Rapid rescreening of all negative gynecologic smears proved more efficient than 10% random rescreening.

The sensitivity of rapid (partial) review of cervical smears.

Rapid review involves a daily rapid (e.g. 30 s) review of all smears not normally double-screened. It has been suggested that the method may increase the sensitivity of cervical cytology by identifying abnormalities not reported on initial screening, true false negatives (TFN). Rapid screening is reported to have high sensitivity for cervical neoplasia when used as a preview tool. To be effective, however, in a review mode it must be able to detect TFN. Several studies have found that many TFN result from factors such as low numbers of abnormal cells or subtle expression of diagnostic criteria. Studies on the sensitivity of rapid screening for detecting TFN would therefore provide a more reliable estimate of its value as a review tool. The sensitivity of rapid re-screening was evaluated using a test set of 200 cases. Each of 15 screeners rapidly reviewed (30 s partial screen) the set over a 2-week period. The set consisted of 129 normal, 28 low-grade squamous lesions (CIN I), 37 high-grade lesions (CIN II, III and adenocarcinoma in situ (AIS)) and six invasive carcinomas. The abnormals included 20 TFN cases. The median sensitivity for abnormalities was 62%. Rapid review was more sensitive for CIN II and CIN III (67%) and invasive carcinoma (66.7%) than for CIN I (53%). Great variation was apparent in the sensitivity for individual screeners, with a range of 41-86% for all abnormalities. The sensitivity for TFN cases varied even more (10-75%, median 35%) and for most screeners was significantly (P < 0.05) lower than for cases which were detected on initial screen (53-90%, median 70.6%). Following this trial rapid review was used routinely for a period of 3 months. In this time 11,413 cases were rapidly reviewed. This led to the full review of 415 slides (3.5%) and the identification of 16 cases of undetected CIN (12 CIN I, three CIN II, one CIN III). Based on current estimates of our laboratory false-negative rate this represents between a quarter and half of the TFN cases of CIN that probably occurred in this period. In conclusion, rapid screening is likely to be significantly less sensitive when used in a review rather than a preview mode. In routine practice the method requires a daily commitment of screener time, but does provide a higher yield of TFN smears than does random review, and allows amendment of these results prior to reporting.

Diagnostic value of endocervical curettage during colposcopy

A retrospective study including patients with cytology, colposcopy and endocervical curettage (ECC) was carried out to compare ECC outcomes to final diagnosis. ECC was performed in 68 cases for a discordance between cytology and colposcopy and in 85 cases because the lesion was incompletely visible. Complete concordance between ECC and final diagnosis was obtained in 123 cases. ECC overestimated diagnosis in eight cases (5 true false positives) and underestimated it in 20 cases (6 true false negatives). Among the latter, ECC failed to recognized invasion in seven cases. Sensitivity, specificity, positive and negative predictive values of ECC to diagnose high grade cervical intraepithelial neoplasia (CIN) and invasive lesions together were 84%, 97%, 95% and 90%, respectively. Outcomes to diagnose invasive lesions were 22%, 100%, 100% and 95%, respectively. ECC sensitivity to diagnose endocervical lesions is satisfactory but its sensitivity to establish the diagnosis of invasion is very low. Consequently, a conization is advisable when ECC has diagnosed an endocervical lesion, especially a high grade CIN.

Analysis of the causes of false negative cytology reports on breast cancer fine needle aspirates

Forty-six (2.9%) false negative reports were recorded among adequate fine needle aspirates from 1609 consecutive histologically proven carcinomas, observed from 1991 to 1993. False negatives were more frequent among younger women (< 40 years = 7.1; 40-49 years = 4.0; 50-59 years = 3.6; 60-69 years = 1.7; > 69 years = 1.5%), lobular invasive subtypes (5.4%), and smaller tumours (pT1a = 4.2; pT1b = 7.6; pT1c = 1.9; pT2 = 2.1; pT3-4 = 1.5%). The latter findings is probably ascribable to better differentiation and less precise sampling of small non-palpable tumours. No significant association was found between the false negative rate and the sampler's or reader's skill and experience. The former finding may be ascribed to the wide use of sonography guided aspiration, even for palpable masses, and the latter to the fact that readers were highly experienced and undergo periodic quality control of individual performance. False negatives were reclassified at reviews as true false negatives, reading errors or inadequates in 27, 11, and eight cases, respectively. The observed findings suggest that in most cases cytological faults were due to the absence of cytological atypia in cells sampled from well differentiated tumours, rather than to misinterpretation or sampling from adjacent normal tissues.

Evaluation of the radioimmunoassay for benzoylecgonine (a cocaine metabolite) in human urine.

The 125I-radioimmunoassay (RIA) for benzylecgonine (cocaine metabolite) in urine was evaluated by comparison with gas-liquid chromatography (GLC) and thin-layer chromatography (TLC) and the Enzyme-Multiplied Immunoassay Technique (EMIT). By RIA, a statistically significant concentration, 2 microng/liter, was observed for urinary benzoylecgonine. The coefficient of variation for the RIA was 2.58+/-0.38% inter-assay and 2.20+/-0.14% intraassay. There was cross-reactivity with cocaine (more reactive than benzoylecgonine) and other members of the tropane family of alkaloids. There was agreement between results by RIA and GLC in 95.5% of the samples, between RIA and TLC in 87.0%, and between RIA and EMIT in 84.5%. The percentage of true false-positives was 3.5% for the RIA in comparison to GLC, 8.8% in comparison to TLC, and 9.1% in comparison to EMIT. True false-negatives were insignificant (0 to 1.0%). GLC and RIA results correlated highly (phi=0.908). GLC, therefore, was the best comparison method for this evaluation study. RIA for benzoylecgonine is sensitive, reproducible, and reliable for the detection of cocaine in urine.