Background: Multi-criteria decision analysis (MCDA) is a decision-making tool that can take into account multidimensional factors and enables comparison of  technologies by combining individual criteria into one overall appraisal. The MCDA approach has slowly gained traction within Health Technology Assessment (HTA) and its elements are gradually being incorporated into HTA across Europe. Several groups of scientists have proposed MCDA approaches targeted toward orphan drugs and rare diseases by including criteria specific to rare diseases. The goal of this article is to provide an overview of the current state of knowledge and latest developments in the field of MCDA in HTA for orphan drugs, to review existing models, their design characteristics, as well as to identify opportunities for further model improvement.Methods: A systematic literature search was conducted in January 2018 using four databases: MEDLINE (Pubmed), EBSCO HOST, EMBASE, and Web of science to find publications related to use of MCDA in the rare disease field (keywords: MCDA/orphan drug/rare disease and synonyms). Identified MCDA models were analyzed, e.g., structure, criteria, scoring, and weighting methodology.Results: Two hundred and eleven publications were identified, of which 29 were included after removal of duplicates. 9 authors developed own MCDA models, 7 of which based on literature reviews intended to identify the most important and relevant decision criteria in the model. In 13 publications (8 models) weights were assigned to criteria based on stakeholder input. The most commonly chosen criteria for creation of the MCDA models were: comparative effectiveness/efficacy, the need for intervention, and disease severity. Some models have overlapping criteria, especially in the treatment cost and effectiveness areas.Conclusions: A range of MCDA models for HTA have been developed, each with a slightly different approach, focus, and complexity, including several that specifically target rare diseases and orphan drug appraisal. Models have slowly progressed over the years based on pilots, stakeholder input, sharing experiences and scientific publications. However, full consensus on model structure, criteria selection and weighting is still lacking. A simplification of the MCDA model approach may increase its acceptance. A multi-stakeholder discussion on fundamental design and implementation strategies for MCDA models would be beneficial to this end. There is an ongoing debate if conventional health technology assessment (HTA) methods are still appropriate for orphan medicinal products (OMPs) and other highly specialized, innovative, expensive treatments –4. The o,Direct treatment costs and effectiveness are the main (and often only) criteria that are taken into account, as well as the impact on the healthcare budget . The eff6.Multi-criteria decision analysis is a decision-making tool that can take into account multidimensional factors and enables comparison of medical technologies by combining individual criteria into one overall appraisal , 20. MCDCore HTA model (v3.0), with an incorporation of MCDA elements from the EVIDEM MCDA framework (v3.0)  . This pik (v3.0) .Palaska published an overview of existing OMP MCDA models in 2014 (poster presentation)  . The grontation) . After cntation) . HoweverThe goal of this article is to provide an overview of the current state of knowledge and latest developments in the field of MCDA in HTA for orphan drugs, to review the existing models, their design characteristics, as well as to identify opportunities for further model improvement. Given the speed at which the orphan drug HTA field is changing, the authors believe a publication with the latest information on the use of MCDA models in orphan drugs is warranted . Focus was laid on studies that discuss the design and practical implementation of MCDA, e.g., the identification of relevant model criteria and weights, scoring methods, assessment, and comparison of drugs through MCDA appraisal.A systematic literature search was conducted using four databases: MEDLINE (Pubmed), EBSCO HOST, EMBASE and Web of Science in January 2018. The search strategy was focused on the use of MCDA in HTA and reimbursement of orphan drugs and methodological aspects of the different models. As many reimbursement/HTA aspects can be expressed in various ways, a high-level search was conducted with only the keywords “MCDA,” “orphan drugs,” and “rare diseases” (and synonyms) to capture all possible relevant publications.The following search strategy was applied in all four databases:*) OR “OD” OR “OMP” OR “ODs” OR (OMPs) OR  OR (rare disease*) OR (rare disorder*)].[MCDA or  or  or  or  or  or  or  or  or  or  or  or  or  or (“multi-criteria decision making”) or (“multi-criteria-decision-making”) or (“multi criteria decision making”) or (“multicriteria decision making”) or (“multiple-criteria decision making”) or (“multiple-criteria-decision-making”) or (“multiple criteria decision making”)] AND [(orphan drugNo time limits were imposed in order to spot trends over time (if any). Only full-text articles and abstracts published by 1st January 2018 written in English were included. All steps of the literature review  were performed by 2 independent researchers.Included in this review were original research publications addressing the following subjects within the area of MCDA for OMP/rare diseases: model creation and adjustment, identification and definition of model criteria, weight elicitation, model validation through MCDA OMP appraisal/testing, and articles on discussing the impact of MCDA application on decision making.Publications that did not address MCDA and OMPs in-depth or as the main subject, as well as publications on the subject of MCDA outside the field of HTA and/or reimbursement for OMPs  were excluded.n = 24; EBSCO HOST n = 98; EMBASE n = 55; web of science n = 34). No additional records were identified using other sources.The initial search resulted in 211 publications . Forty seven records were screened by reading full-text articles, out of which 13 were excluded which did not have MCDA as the main subject or in case the publication had a more theoretical nature (not research-based) or contained only limited information on MCDA.Thirty four publications were included in qualitative synthesis. The authors decided to remove an additional 5 abstracts which had overlapping results and outcomes with identified full-text articles.Twenty nine publications were included in the systematic review, i.e., articles concerning MCDA in the field of reimbursement/HTA processes of rare diseases and orphan drugs: 13 full-text articles and 16 posters. Sixteen publications dealt with the creation and testing of MCDA models and 6 publications were of a more general nature describing MCDA principles  the authors assigned weights to the individual criteria in their models, based on stakeholder interviews via questionnaires or in workshops but also based on the authors' own insights. The most commonly used methods for weighting and scoring in the reviewed publications were: simple additive weighting  and hierarchical point allocation. Three criteria were consistently rated as the most important : disease severity/burden  included the complexity of the manufacturing process [Schey et al. , in medical benefit-risk assessments or even the use of MCDA in other industries could be beneficial to get a complete picture of the methodology, its advantages and drawbacks. This could also give valuable insights on practical hurdles that exist for implementation of MCDA into decision-making processes, as well as relevant experiences and best practices.The literature search strategy was designed to be broad with only 3 keywords, albeit designed to capture all possible variants of these keywords. A potential methodological shortcoming is that not all relevant publications may have been found due to articles missing the specific keyword of “rare disease” and/or “orphan drug,” e.g., research articles dealing with MCDA in a specific rare disease.A systematic review format was used, no qualitative assessment was done of the different MCDA models, i.e., using a rating scale. Studies differ in design and scope and many models have both strengths and weaknesses. A valid comparison would require well-defined and objective metrics and valuation. Instead, the main focus has been laid on an assessment of the different criteria used in the MCDA models, general model structures, and possibilities for optimization of an MCDA model that is suitable, predictable and straightforward to use in practice. A more detailed analysis of model criteria and design considerations is given below.Recently, a number of authors have expressed critical views on the current MCDA frameworks and pointed out several flaws and drawbacks of the used design and scoring methodology, as well as proposing new models or alterations to correct these faults , 59, 60.While it may seem methodologically or ethically desirable to include as many rare-disease specific components as possible into the MCDA model for orphan drugs, careful attention must be paid to criteria selection and weighting, to ensure meaningfulness, appropriate representation and to prevent overweighting and double-counting. This is also underlined by the ISPOR MCDA guideline, which specifies that criteria should be complete, non-redundant, non-overlapping and independent of preferences, as well as being unambiguous, comprehensive, direct, operational, and understandable .Trip's model contains drug effectiveness, cost-effectiveness and budget impact, as well as annual costs of the drug per patient, with overlap and therefore possible overweighting of costs and/or effectiveness in the scoring. Similarly, Kolasa et al.  and other contributions to patient care that can be relevant for disease management. The Benefits criterion can capture effects brought on by enhanced pharmaceutical formulations , less burdensome dosing schedules or other impact on treatment burden , which can be relevant for certain rare disease treatments. The authors recommend a structured approach to the Benefits criterion with pre-specified sub-criteria. Including a field that captures “treatment compliance” would be beneficial, as this is an important factor for treatment success, and especially for costly orphan drugs the financial impact of non-compliance could be large. None of the identified models included compliance/adherence as a criterion.Benefits is a broad “bucket” criterion that can contain a range of clinical advantages such as treatment convenience  as this is a patient-reported measure of effectiveness that is additive and possibly overlapping. Models including PROs as a separate criterion should aim to prevent overweighting of clinical efficacy and other treatment benefits through PRO scores.Wagner et al's. , 25, 43 While it is understood that rare diseases should be treated fairly and need a special approach, it is difficult to directly translate  “population size” into a factor that is relevant to the value of a treatment and thus the MCDA outcome. Should the largest affected population receive priority treatment, which is a utilitarian view, or does the rarity of a disease justify a “compassionate” application of healthcare and therefore a higher priority above common diseases? This immediately complicates scoring and weighting: is less more or is more more?The disease prevalence threshold in the EU for an orphan drug designation is well-defined at ≤ 5 per 10.000. Since it is expected that OMPs will most likely be compared directly with other similar (orphan) drugs, the relevance of population size on the MCDA outcome is limited. E.g. does a prevalence of 3 per 10.000 make a difference for the MCDA score over 2 per 10.000, even though it represents a 50% population size increase? Gilabert-Perramon et al.  also fouAdditionally, if the total budget impact of the treatment is included as a cost component in MCDA, it could be argued that the impact of “rarity” is amplified, e.g., possibly receiving a high score on “rarity” and a high score on “budget impact” . While this can be the aim of a model, it should be considered during design/weighting and clearly expressed to assessors during scoring.Since population size as such is difficult to score and might not have a relevant impact on the MCDA outcome anyway , one can argue to not include this criterion, as Iskrov et al. , Sussex The argumentation for whether rare diseases should be treated differently by the population as a whole is essentially the same as described for “Disease Population Size.” It is difficult to generate an objective, meaningful value-score out of population priorities, and it should be considered that “Unmet need” or “Disease Severity” could also cover the “Population priority” aspect.“Unmet  need” is expressed differently in the various models, such as Availability of treatment /Unmet medical need or “Uniqueness of indication”, e.g., no strict definition exists. Unmet need can incorporate several defining criteria: patient population size, disease severity and lack of effective and/or approved treatments, which should be clearly defined, again to prevent overlap. Orphan drugs, by definition, target a disease population that has no effective and approved treatment; this is a requirement from regulatory agencies as EMA and FDA to be granted an orphan designation (exception: when a drug shows “significant benefit” over an existing orphan drug). In some cases, food products or nutritional supplements can be used to manage or alleviate symptoms of the disease  or food for special medical purposes  and OTC medication . As food products, supplements and OTC products are usually out of scope of healthcare coverage and don't have established efficacy and safety profiles , one can argue to not take these products into consideration when assessing the unmet medical need for OMPs.Comparative Effectiveness” in MCDA for orphan drugs can be questioned, as per definition there is no approved treatment available in orphan indications, and direct comparisons will rarely happen. Any (indirect) comparator would likely include off-label drugs  and other non-approved treatments, which could limit the validity of such a comparison. It can be argued that the effectiveness or overall “value” of OMPs can be compared with drugs for similar orphan indications or drugs for indications with similar defining properties . The same goes for comparative safety. Moreover, the efficacy and safety of the drug (and a benefit-risk outcome) have already been established during the marketing authorization application, and in case of an acceptable outcome, an approval  would be granted. When assessing the efficacy/safety during MCDA one should take the scientific assessments of regulatory agencies into consideration, as clearly contradictory outcomes would be debatable.Including the criterion “Generation of robust clinical evidence, endpoint validation and assessing clinical outcomes are inherently problematic in small population groups, which reduces the suitability of “Quality of Evidence” criterion in MCDA assessments for OMPs. Disease severity and progressive disease limits the use of placebo-controlled trials in many rare diseases and data sets will generally be small. Evidence quality by itself would not lead to meaningful differentiation between many (ultra) orphan drugs and could automatically disqualify many orphan drugs if they were to be directly compared to drugs for common diseases with a perceived “adequate” evidence quality. The authors think that a proper approach would be pragmatic and aim for certain flexibility, i.e., to allow for evidential uncertainty when this cannot be reasonably avoided, within pre-defined limits. Regulatory agencies are willing to accept a reduced burden of evidence in certain situations , but often under specific conditions that oblige manufacturers to generate additional evidence on efficacy, safety and practical use . Accordingly, payers could approach HTA and reimbursement in case of evidential uncertainty in a similar fashion, i.e., allow early but “conditional reimbursement” for certain promising treatments, with the requirement to generate real-world evidence and perform an updated pharmacoeconomic assessment periodically. An example of a country where conditional reimbursement was used is the Netherlands, but due to the limited number and low quality of applications it has been replaced by a more general subsidy program focused on small and medium-sized enterprises .Garau et al.  and PaulA major hurdle for orphan drug developers is generating a return on investment, due to the small patient population that will use the final product. However, most HTA models take a societal perspective or a payer-centric view and do not put emphasis on factors that are important for developers of orphan drugs. In contrast, the EU regulatory framework specifically incentivizes orphan drug development by providing a range of regulatory and commercial benefits for OMP manufacturers. To align EU HTA processes with these incentives, MCDA criteria would be needed that represent a similar benefit/valuation for manufacturers of orphan drugs. Several authors have tried to capture “innovation” as a factor, e.g., Gutierrez et al.  providedmanufacturing complexity via the cost of biotech processes, complexity of drug synthesis based on the number of “chemical transformations” and the necessity to use “separation techniques” for chemical intermediates. To measure “Advancement of technology”, Kolasa et al. , open-label trial, use of historical control arms) also represents a type of innovativeness and R&D investment. However, trial design would typically be already taken into account through the Quality of Evidence criterion or weight-factor (where a double-blind RCT represents the golden standard), so double-counting would need to be carefully avoided if this were to be considered.A possible methodological flaw in several MCDA models is the incorporation of both costs and value (benefits) into one aggregated MCDA end-score, i.e., one additive score containing disease characteristics, treatment outcomes and cost-related criteria. Using such an aggregate score creates difficulties in assessing and interpreting the final MCDA outcome and complicates comparison of technologies. Since economic consequences are highly dependent on the local healthcare system and economic factors , separating criteria that define the “Value of the intervention” from those defining “Economic consequences”  would allow for generating more objective, meaningful and understandable MCDA scores. Having a distinct “Value-Score” and “Cost-Score” of the treatment could simplify models, ease interpretation and create the flexibility to easily transfer outcomes to the national HTA level (transferability). For example, a treatment's value-score (for use in HTA) could be assessed centrally by the EMA or any other appointed scientific/regulatory and be transferred to the national HTA body for use in MCDA or other methods. The selection and definition of cost-related factors for HTA and the actual cost-calculation is performed nationally, where the cost- and value-scores can be weighed for decision-making on local healthcare coverage. Such an approach would also be aligned with the EU proposal for a new HTA Regulation  which deHow to balance value vs. costs in healthcare budgets is one of the key considerations made by several researchers, especially whether the economic assessment should be based on opportunity-cost analysis or more traditional cost-effectiveness analysis. In situations where budgets are finite, as in healthcare systems, opportunity-cost analysis allows for the evaluation of resources that cannot be spent due to expenditure elsewhere, which stimulates the “replacement” of older interventions by newer ones with a lower opportunity cost. The opportunity cost approach plays a central role in Paulden et al's.  decisionMultiple mathematical and statistical methods can be used for scoring, weighting, analyzing and comparing alternatives in MCDA models. The theoretical basis for the models is rarely discussed in most of the reviewed studies. An ISPOR task force has issued 2 publications on best practices in MCDA to guide model developers in 2016 , 61. HowA recent EU survey  shows thOver the last 10 years a range of MCDA models for HTA have been created, each with a slightly different approach, focus and complexity, including several models that specifically target rare diseases and orphan drugs. These models have slowly progressed based on pilots, stakeholder input, sharing experiences and scientific publications. However, full consensus on model structure, criteria selection, and weighting is still lacking. As shown in this and other publications, a more fundamental discussion on the methodological and mathematical design aspects of MCDA models is ongoing and needed. Initiatives such as the EVIDEM framework and the MoCA project help to create momentum and standardization, but have not led to any significant EU-wide implementation. This shows that apparently hurdles still need to be overcome and model improvements are necessary. The planned EU HTA regulation could have some positive spill-over effects to stimulate the development and harmonization of MCDA in HTA. Given the differences in national healthcare and reimbursement systems, as well as local variations in economy and rare disease policies, HTA models that are flexible and adaptable would be required. MCDA can capture factors beyond standard cost-effectiveness analysis and offer a range of possibilities that would be suitable for rare disease HTA.The authors have attempted to highlight some of the problems that exist with the design of current MCDA models, with a review of commonly used model criteria and how to generate more clear and meaningful results with them. As it stands, models are often unclear and results difficult to interpret, which warrants a simplification of current designs with fewer and well-defined domains and with less overlap between criteria. A strict separation of value from costs in MCDA models would be increase the flexibility, clarity of the model, and transferability of the results, which could aid implementation. Further research, model improvement and validation, practical application and multi-stakeholder discussion are necessary to bring about consensus and to fulfill the potential that MCDA promises in healthcare HTA.AB-K contributed to conceptualization, research, methodology, writing—original draft preparation, review, and editing. MC contributed to methodology, supervision, writing—review, and editing. CK contributed to writing—review, research, and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Access to information about prenatal screening is important particularly in light of new techniques such as non-invasive prenatal testing (NIPT). This study aimed to develop and examine the acceptability of a low literacy decision aid (DA) about Down syndrome screening among pregnant women with varying education levels and GPs.We developed a DA booklet providing information about first-trimester combined testing, maternal serum screening, and NIPT. GPs and women participated in a telephone interview to examine the acceptability of the DA and measure screening knowledge before and after reading the DA. The knowledge measure was designed to assess whether women had understood the gist of the information presented in the decision aid. It comprised conceptual questions (e.g. screening tells you the chance of having a baby with Down syndrome) and numeric questions (e.g. the accuracy of different screening tests).n = 22, 76%), and ‘very’ informative . Overall, women’s conceptual and numeric knowledge improved after exposure to the DA, from 4% having adequate knowledge to 69%. Women’s knowledge of NIPT also improved after receiving the decision aid, irrespective of education. Most GPs found it ‘very’ clearly presented , and that it would ‘very much’ facilitate decision-making .Twenty-nine women and 18 GPs participated. Regardless of education level, most women found the booklet ‘very’ clearly presented  contains supplementary material, which is available to authorized users. Screening in early pregnancy for foetal abnormalities is an established part of routine care in Western countries . Some coFollowing the discovery of cell-free foetal DNA in the mother’s blood, non-invasive prenatal testing (NIPT) is steadily becoming available to screen for Down syndrome in early pregnancy , 8. NIPTAccess to decision support information in early pregnancy is essential for making informed decisions, particularly in light of the availability of NIPT and the perception that it is “just a blood test” , 21. TheDecision aids (DAs) are tools designed to help people to make informed health decisions by explicitly stating the decision, providing information about the potential benefits and risks, and by clarifying values . In prenA key challenge when designing health information is making sure that it is accessible and understood to people with different education and literacy skills . Even woTo address the gaps highlighted above, this descriptive study aimed to: (1) develop a low literacy DA about prenatal screening for Down syndrome including NIPT, to complement counselling by a GP or other antenatal health care professional, (2) examine the acceptability and comprehensibility of the DA among GPs and among women with different education levels, and elicit suggestions for improvement, and (3) measure women’s screening knowledge about the different screening tests available (including NIPT) before and after receiving the decision aid.The DA was developed by a multidisciplinary steering committee  of health professionals and researchers with expertise in epidemiology, genetics education, genetic counselling, psychology, DA development, and maternal foetal medicine. Existing Australian prenatal screening resources and the International Patient Decision Aid Standards (IPDAS) informed the content –35. The http://www.psychosocialresearchgroupunsw.org/decision-aids.html.Various low-literacy design strategies were applied, including; plain language; colour coding; glossary of medical terms; visual illustrations; simple medical diagrams; and providing contextual information before factual information –40. The GPs were invited to provide feedback on the DA and assist in recruiting eligible women. Invitation letters were sent to 320 GPs working in antenatal shared care listed on a hospital database in South Western Sydney, New South Wales (NSW), Australia. South Western Sydney is a metropolitan part of Sydney, with a higher proportion of lower socioeconomic groups compared to other areas of Sydney . In AustInterested GPs returned an expression of interest form and were visited by researchers (AC and SS), who explained the recruitment process, obtained written informed consent, and provided information packs . GPs were asked to invite all eligible women, until the target sample size of 30 was reached. In our previous decision aid work, a sample size of 30 has been found to be suitable for obtaining feedback on the acceptability and comprehensibility of DAs , 45. We GPs took part in a 30-min telephone interview using closed/structured and open-ended questions to obtain feedback on the DA. The current study reports the responses to the structured questions; the qualitative data will be reported in a separate paper. For participation, GPs received continuing professional development points from the Royal Australian College of General Practitioners.Eligible women were invited by their GP and given an information sheet. Women were eligible if they were aged 16 years or older, were able to speak English and equal to or less than 13 weeks and 2 days of gestation. This cut-off time was chosen because in Australia combined first trimester screening is carried out between 9 weeks and 13 weeks (plus 6 days). This cut-off point enabled us to recruit women slightly later on in gestation to widen the recruitment window . Women wParticipants were recruited between 2014 and 2015. Ethics approval was obtained from the South Eastern and South Western Sydney Local Health District Human Research Ethics Committees (ref number: 12/219).Socio-demographic data were collected from GPs. Closed questions  adapted from our previous research were used to examine perceptions of its length, balance, clarity, and usefulness . Some opData on age, marital status, educational level, country of birth, years lived in Australia, first language, employment status, occupation, previous pregnancy outcomes and screening experience were collected.Closed questions using Likert rating scales examined the acceptability of the DA in terms of its length, balance, clarity, and amount of information. Comments on the illustrations, colour coding, diagrams, and worksheet were elicited using open-ended questions, and participants were asked to offer suggestions on how to improve the DA.Knowledge is a key component of informed decision-making. Prenatal screening knowledge was measured to identify the extent to which women’s knowledge changed before and after exposure to the DA, and examine whether the resource would help inform women’s decision-making during pregnancy. The knowledge questions and marking scheme were informed by Fuzzy Trace Theory, a dual-process theory which proposes two ways in which people process and store information in their memory: (i) processing and remembering the bottom-line meaning (‘gist’), and (ii) processing and recalling information precise details (‘verbatim’) . When maData were analysed using SPSS 24.0 , 72% were female, 50% were born in Australia, and 40% had more than 20 years’ experience  – undergraduate or postgraduate degree and, (ii) Lower education  – completed secondary/ high school education or had successfully completed a Higher School Certificate, or trade/technical/vocational qualifications.The mean age of the women was 32 years (range 25–40 years) , ‘very’ easy to read , ‘very’ useful , and ‘very’ appealing  . The majority of GPs felt that the DA presented a balanced view of prenatal screening , and would ‘very much’ assist women/couples in helping them to better understand about screening  and facilitate their decision-making .Most GPs felt that the information was ‘very’ clear . Just over half of GPs  thought it would be ‘very’ feasible to implement the DA into practice, whereas the remaining GPs felt it would be ‘somewhat’ more challenging . Half of the GPs described the information in the DA as just the right amount , and the other half thought it would be ‘too much’ for women .Most felt the DA would make it ‘somewhat’ or ‘much’ easier to communicate to women about screening , and that it took them less than 30 min to read . Around half of the women reported that ‘all’ or ‘most’ of the information was new to them . Most women felt the DA presented a balanced view of screening , although a slightly higher proportion of women with higher education thought it was encouraging screening  compared to those with lower education . Most women thought the amount of information was ‘just right’ , with only a few finding it to be ‘too much’ information .Overall, women reacted positively towards the DA Table . The majn = 22, 76%), ‘very’ informative , ‘very’ easy to read , and ‘very’ useful  . The majority of women felt the booklet was ‘very’ helpful in increasing their understanding of the options . Around half of the women reported it being ‘very’ helpful in clarifying their decision-making  and reaching a decision . Just over a third of women reported completing the personal worksheet .Most women found the booklet ‘very’ clearly presented (%) Table . SlightlAll of the women found the font size appropriate. The colours were described as ‘bright’, and ‘consistent’. The illustrations and diagrams were generally well received; being described as ‘appropriate’, and ‘a good mix of cultures’. However, a few women did not like the illustrations and found them ‘condescending’ and too ‘upbeat’ considering the serious nature of the topic.The summary sheet, timeline, worksheet and glossary of medical words were described as ‘useful’, and helping to ‘put it into perspective’. The 100 dot-diagrams  to 18.3 Table . ConceptBoth women and GPs had useful suggestions on how to improve the booklet. The following revisions were made in accordance with their feedback. We included a summary page comparing the accuracy and potential risks (i.e. miscarriage) of the different types of screening and diagnostic tests so the reader had all the information in one to which they could refer to in their decision-making. Both women and GPs wanted more practical information on where NIPT could be done and who to ask about it; we included a list of questions about NIPT that women could ask their GP, or other antenatal health professional. Some women were interested to know where they could find more information on the practicalities or impact of raising a child with Down syndrome. As such, in our revisions, we provided details of several resources produced by Down syndrome Australia. Some GPs felt the booklet should explain that screening requires medical referral, and clarify that screening identifies other chromosomal conditions. Throughout the booklet, we made some wording changes in accordance with Down syndrome Australia protocol on how to communicate with the public about Down syndrome. For example, we replaced the term ‘risk’ with ‘chance’, and ‘problem’ or ‘disease’ with ‘condition’. Based on GP feedback, we described diagnostic tests as ‘definite’ tests and replaced ‘detecting Down syndrome’ with ‘identifying Down syndrome’. We also reworded the 100-dot diagrams to clarify that the diagrams represented 100 pregnant women carrying a baby with Down syndrome.This article describes the development and acceptability of a low literacy DA about Down syndrome screening. The DA was well received by women with different education levels and GPs. Women’s knowledge of the different types of screening tests, including NIPT, increased after exposure to the DA. Most women felt the information was very clearly presented, easy to read, informative, and rated the amount of information and length favourably. The DA was considered to be relevant, with most reporting they would recommend it to others. Similarly, most GPs reported the DA as clear, and that it would assist women in decision-making.Although conceptual and numeric knowledge increased for both higher and lower education groups, a slightly higher proportion of women with higher education were found to have adequate knowledge compared to those with lower education. Although this is a small sample, it nonetheless echoes previous work showing that women from lower education groups experience greater difficulties making an informed decision . SimilarBoth women and GPs reviewed the DA positively, and there were few discrepancies in their views towards it. However, they did differ with regard to the amount of information, with half of the GPs thinking there was too much information, yet most women thinking it was just about right. Women expressed the need for more experiential information about living with a child who has Down syndrome. The final version includes website links with information about this. It is not uncommon for health professionals to underestimate how much information patients want to receive, possibly through fear of overloading patients, or underestimating their understanding .Not all GPs agreed that the DA would be easy to implement and some felt it would not necessarily facilitate communication. The challenges of implementing DAs in clinical practice are widely reported –56. AlthOur results showed that around two-thirds of women reported not using the values clarification worksheet. Perhaps the information on its own without a values clarification exercise might be enough to improve knowledge and enhance decision-making , 59, 60,We note that GPs were the only health professionals involved in the study. Including other health professionals  would have been useful to explore the diversity of perspectives. One study observed that health professionals varied in their attitudes towards using prenatal screening DAs; midwives seemed more positive about using DAs compared to GPs and obstetricians .At the time of the study, NIPT was on the cusp of being implemented into the Australian healthcare system, predominately in the private health care system with test results being sent to offshore laboratories on a user pays basis with no reimbursement. At present, NIPT is more widely available in both the private and public healthcare system, and although it is less expensive than it used to be, it is still offered with no reimbursement. It is possible that discussions with health care professionals about NIPT may have influenced women’s knowledge and understanding about NIPT, and women may have paid less attention to the decision aid because NIPT was too expensive for women to consider a viable option. However, we note that some GPs in our study were not fully aware of the availability of NIPT and found the decision aid to be informative in improving their own knowledge. Further, our results showed that women’s knowledge of NIPT increased after exposure to the decision aid and they were able to correctly answer questions about accuracy of the NIPT that would have required reading the decision aid.This study has a few limitations. Firstly, despite efforts to recruit partners to the study we were not successful. However, most women in the current study reported showing the DA to their partners, indicating that they valued their involvement. Similarly, previous research has shown screening decisions are often made by couples together , 61, 62.Secondly, although we made efforts to recruit women with varying education levels to ensure the tool was acceptable to different education groups, we encountered difficulties recruiting women from lower education groups. The length of recruitment was extended due to difficulties recruiting this group. This is perhaps not surprising given that lower socioeconomic groups are generally under-represented in health and medical research . In addiThirdly, given the aims of the study were to provide descriptive data on the acceptability of the DA, the results should therefore be considered as preliminary. The small sample size in each education group meant that we were underpowered to perform statistical analyses to detect any statistical differences between the two groups. At this stage, it is not possible to make conclusive statements about the actual effect of the decision aid without a randomised controlled trial with a larger sample, to evaluate the efficacy of the DA compared to standard information. This will provide valuable evidence on the effect of the decision aid on informed decision-making , and enable us to generalise the findings to populations with different education levels.Finally, in line with previous work , there wThe DA was found to be acceptable, comprehensible, and useful to women from different educational backgrounds and GPs. Women’s knowledge about screening, including NIPT, increased after exposure to the DA. The next steps will be to further test the DA among women with different health literacy skills, and then evaluate the efficacy of the DA on informed decision-making  compared to standard information in a larger sample. It would also be important to identify strategies for how the tool could be more broadly used and implemented by GPs and other health professionals.This is one of the few prenatal screening DAs to provide information about NIPT. It has the potential to provide prospective parents with clear and easy-to-read information, and complement existing information presented by health care professionals. A formal evaluation of the efficacy of the tool (compared to standard information) is necessary before it is made available.Although all participants spoke English, around one-third of participants were bilingual. If translated into different languages, the DA could provide culturally and linguistically diverse (CALD) populations with a tool that is accessible in their own language and help to address the potential communication challenges. Future work could also focus on translating the DA into different languages to address the needs of those from CALD backgrounds.Future work is also needed to identify and overcome the barriers to implementing DAs, with studies focused on identifying the contextual and facilitative mechanisms that could influence the implementation of the DA . The potAdditional file 1:Knowledge scoring scheme – questions and scoring scheme for the knowledge measure assessing conceptual and numeric knowledge of prenatal screening. (DOCX 20 kb)


Gregor Mendel’s crossing experiments in pea are the foundation of classical genetics, but since the importance of his 1866 paper was not understood until after long after his notebooks were burned, we know little... Pisum lectures by 4 years. These articles describe Mendel as a plant breeder and a horticulturist. We argue that Mendel’s initial interests concerned crop improvement, but that with time he became more interested in fundamental questions about inheritance, fertilization, and natural hybridization.Despite the fact that Gregor Mendel is generally respected as the founder of genetics, little is known about the origin of and motivation for his revolutionary work. No primary sources are known that discuss his work during the period of his pea crossing experiments. Here, we report on two previously unknown interconnected local newspaper articles about Mendel’s work that predate his famous  GREGOR Mendel (1822–1884) is recognized as the founder of genetics because of the garden pea and common bean crossing experiments described in his famous article “Experiments on Plant Hybrids” (1866). Although this paper is now > 150 years old, it is still intensively studied. Recently, new English translations have appeared: a Darwinian interpretation  and one During his life, Mendel’s work was not appreciated and his notes were destroyed after his death, so when his work came to light in 1900, there were few primary historical sources left and therefore relatively little was known about his biological work and reasoning. While Mendel’s experiments and insights are treated as foundational in virtually all textbooks of genetics, Mendel as a scientist remains a rather mysterious figure. In fact, the major Mendel biographies provide hardly any information about his work in the crucial period of 10 years (1854–1863) during which Mendel performed his famous crossing experiments with peas . The lacpost hoc interpretation that is not in line with Mendel’s original intentions. Most of these views share the “orthodox interpretation” that Mendel was trying to understand the rules of inheritance . In striHieracium (hawkweeds)   and two wkweeds) , 1854. Twkweeds) , so we oeriments  and can Hieracium experiments, which took place in the 8 years following his Pisum work (1866–1873). Furthermore, 18 letters that Mendel wrote to his relatives and friends are preserved (https://www.darwinproject.ac.uk/letters/darwins-life-letters).A second primary source are Mendel’s letters. Letters are more like diaries and often describe thoughts and motivations. Some of Mendel’s correspondence with Carl Nägeli, professor of botany in Munich, is known, including 10 letters that were published by reserved , but in A third primary source are the first-hand accounts of people who met Mendel during his life. In the first decade after the rediscovery of Mendel’s work, many of his pupils from the secondary school were still alive. Neuigkeiten about the Pisum lectures Mendel gave in February and March 1865 were discovered by Finally, a fourth source are newspapers from Mendel’s time. Two short reports in the local newspaper Neuigkeiten” (“News”), a daily newspaper of Brünn, the capital of Moravia, where Mendel lived . It is a copy of an article in Mährischer Korrespondent (M. K.) (Moravian Correspondent), another newspaper in Brünn and its surroundings. The Brünn newspapers were printed in German gothic fonts, which are often not well converted by Optical Character Recognition (OCR) software. A search for “Mendel” or “Mendl” did not find the article, but a search for “Befruchtung” (fertilization) did. The OCR reads Mendl the first time as “Wenol” and the second time as “Mc »dl,” explaining why the first searches were fruitless. The article may not have been found in the paper versions in the past, because it does not have a separate headline but is part of a feature “Brünner Zuschauer” (Brünner Spectator). The corrected and translated text reads as follows:The first article  appeared2, cucumbers, and beans, are high towering bushes that are distinguished by a massive production of fruit which, in size and taste, leave nothing to be desired. For the cultivation of these plants mainly seeds from abroad were used. Of the foreign vegetables so far the New Zealand spinach, which thrives in our soil, was acclimatized. The very fleshy leaves not only contain more nutritious substances than the now cultivated varieties, but the plant is characterized by luxuriant growth, so that some specimens cover their rather large experimental plot almost entirely with their leaves. Until now, the experiments carried out with potatoes were less successful. The plants showed a very vigorous development, but the fruits3 started to rot and so far no remedy has been found. Professor Mendl has temporarily extended his experiments [also] to several species of flowers, which up to now have had to be imported at great expense from abroad. The carnations and fuchsias, of which the Professor grew several 100 pots, stand out by their abundance and colorful splendor in an astonishing way. Considering the efforts and diligence which these experiments require to obtain a successful result, one must give all recognition to the professor’s endeavor. The substantial amounts of money that are currently spent on buying seed abroad can better be preserved for domestic production , another local newspaper, arguing that the reporter had overstated the importance of Mendel’s work for the local economy  of carnations and fuchsias is an old and generally known practice, currently well known to every thinking garden assistant. The first, the scarlet fuchsia, ersisted .This second article is rather negative about Mendel’s horticultural work, although it purports to recognize its scientific value: “we honor every endeavor to approach truth in a practical manner.” This remark is intriguing, since it suggests that Mendel was empirically solving a scientific question, which in this instance would have been the understanding of the inheritance of traits.Pisum experiments, and are the only significant sources so far about his work between the finishing of his University studies at Vienna in July 1853 and the two pea lectures in February and March 1865. The articles in local newspapers reflect the interest from the general public for the type of work that Mendel was doing. These newspapers were widely read and together had a daily circulation of > 6000 copies  and fuchsia plants. These crosses with Dianthus and Fuchsia can be seen as the motivation and inspiration that Mendel speaks of at the beginning of the 1866 paper. Carnation experiments are mentioned in the 1866 article and Mendel’s interest in fuchsia was known. In two group photos of that time (∼1862), he stands among the other brothers of the Augustinian Community of St. Thomas Monastery in Brünn with a fuchsia flower in hand (Prälat Mendel)  .Phytophtera infestans, was a major problem throughout Europe in the middle of the 19th century, and reports on “Kartoffelfäule” regularly appear in the Brünn newspapers of those days. In one of the surviving letters to his parents, dated December 28, 1851, Mendel writes that to his dismay he heard that the potato disease had spread to the region where his parents lived , carnations, a.s.o.) etc.”  etc.” , p110. IIn 1855, Mendel became a member of the Natural Science Section of the Agricultural Society in Brünn. Napp was active in the Pomological Section, suggesting that Mendel’s interests had become purely scientific, possibly because of his university education and reflecting Napp’s earlier call for a physiological study of inheritance. In the year of the newspaper articles (1861), the Natural Sciences Society split from the Agricultural Society, with the aim of better promoting pure science. Mendel switched to the new Natural Sciences Society, while Napp became chairman of the Horticultural Association, which replaced the Pomological Section of the old Agricultural Society. In 1863, Mendel was chosen as a member of the Horticultural Association . Later, Pisum lectures in February and March 1865 at the Natural Science Society and not at the Horticultural Association. Mendel was indeed interested in plant improvement, as reflected by his membership of the Horticultural Association, but his lecture was not given to that society and was instead given to the one with broader scientific interests.Mendel held his famous Brünner Morgenpost wrote: “The relevant observations were mostly made on Papilionaceae (a family that according to well-known researchers is not very suitable for hybridization)”11 ”11 , suggestTaken together, Napp and Mendel covered both the pure and applied science related to breeding, crop improvement, and genetics; it is hard to imagine that they did not talk to each other about this subject. In July of 1867, Abbot Napp died and Mendel was elected as his successor in March 1868.Pisum crossing experiments, rather than on the organism as a whole. This choice was a departure from the practice of previous hybridizers such as Josef Gottlieb Kölreuter and Carl Friedrich Gärtner, as was his choice to study intraspecific hybridization instead of interspecific hybridization.We can see from these two newspaper articles that Mendel had a background in breeding and note that the breeders  in Brünn were concerned with how to select the best individuals for (rather than from) crosses. The issue was whether these individuals should be selected because of individual characteristics or an assessment of their overall quality. Mendel had studied combinatorial mathematics in Vienna, under Ettingshausen, so this set of interests may have led him to focus on individual traits in his Pisum was suitable for the study of individual traits, for example from the work of Thomas Andrew Knight (1759–1838). In his 1866 paper, Mendel gives three reasons for selecting Pisum, and these are the reasons given by Versuche und Beobachtungen über die Bastarderzeugung im Pflanzenreich  and traits ; these words are used mutually exclusively in different paragraphs in the Pisum paper. The elements were nonblending; beyond this property the physical form of the elements was not specified, nor did it need to be.Mendel will have known that zenreich , Mendel zenreich . Mendel Hieracium. Based on detailed analysis of Mendel’s letters to Nägeli, we have recently argued that the traditional interpretation that the Hieracium crossing experiments were intended to repeat the Pisum experiments, and therefore frustrated Mendel, is wrong , which contrasted with constant hybrids, which produced nonvariable offspring and of which Mendel thought he had found an example in is wrong . With Hivs. hybridization, speciation, and the stability of species and hybrids. All these reflect also Mendel’s interest in pure science. According to the report of the second Pisum lecture in the Mährischer Korrespondent, Mendel first gave an introduction to (what was known about) “the cell and the reproduction of the plants by fertilization.” before he presented his own research .” . I expect that (when inbred) they would sooner or later be found to vary once more. “A” for instance has half “a” in its body [bred out Aa] and when inbred cannot lose that element.” Furthermore, Mendel’s interest in inheritance and its mechanism is clear from his annotations in his own copy of the German translation of Darwin’s The Variation of Animals and Plants under Domestication (1868). Most of these annotations can be found in the penultimate chapter of volume 2, dealing with Darwin’s pangenesis theory of inheritance (Although the word inheritance was used only once in the text of the asis]).” . Howevereritance . That Meeritance , p194.Hieracium studies became a daunting task. While Mendel had produced ca. 200 Hieracium hybrids, this had been a huge effort involving many thousands of hand emasculations and cross-fertilizations , much less so in the variable hybrids (Pisum)], this does not detract from the possibility of his having other concerns. The newly discovered newspaper articles show that Mendel was actively engaged in plant hybridization for the development of useful varieties, and we know that his first two publications reveal an interest in plant productivity. We fully accept the view that Mendel must be seen in the context of his time and environment. We think that this must take account of Mendel’s immediate environment, especially that of the Augustinian community of St Thomas’ monastery, and notably Abbot Napp who supported Mendel and posed some basic questions about inheritance. In this context, proposing that Mendel was interested in inheritance is not an “inflated whiggish” interpretation (The revisionist view, which diminishes Mendel’s role in the development of our understanding of the science of inheritance, is popular among historians and sociologists of science. It is also promoted in popular science books (for example: retation , but groTo summarize, we think that Mendel’s interest evolved from being that of a hybridizer, motivated by practical goals, to that of a scientist motivated by fundamental questions. The basis for this had already been laid during his studies at the university and was clearly catalyzed by his Abbot but, perhaps, also, in 1863–65, by his reading of Darwin.


Employing a generalized Riccati transformation and integral averaging technique, we show that all solutions of the higher order nonlinear delay differential equation Our attention is restricted to the solutions of equation , then there existsrespectivelysuch that, for all sufficiently larget, forandforFurthermore, ifthenfor all sufficiently larget.Suppose that the functionthen both of the following statements hold: (i)Ifandforthen(ii)IfwhereorthenThe statements are obvious, which can be easily checked, we therefore omit the proof here.Suppose thatnis a positive integer, forandThen both of the following statements hold: (i)Ifthen there existandsuch thatfor(ii)Suppose thatthen there existandsuch thatforSuppose first Now we suppose that t approaches to infinity. Throughout this section we will suppose that one of the following conditions holds:In this section we present some sufficient conditions which guarantee that every solution to equation  oscillatSuppose that equation Suppose tequation  is oscilSuppose that equation  on the in with If equation , we knowt on both sides of the above inequality, we deduce that, for By using equation , 3.4), , 3.4), , and Lemion with  valuing Therefore we know n, we deduce that First we prove Theorem n.We prove First we prove for the special case equation , we gets to t on both sides of (ii)H has a continuous and non-positive partial derivative on  then H is said to belong to ℜ. □If a function Suppose that equation (is non-oscillatory and condition (or (holds. We further suppose that there exist two functionsandsatisfyingwhereFor the casewe further assumeforThen any solutionof equation (is oscillatory orasequation  is non-oondition  or 3.2)Suppose tequation  is oscilSuppose that equation  on the iIf n with We define t) as in , i.e.,\equation , we get milar to  holds foombining , 3.4), , \documeFrom inequality , we deducts with . The remSuppose that equation Suppose tfined as  in TheorThen any solutionof equation (is oscillatory or satisfiesasequation  is oscilSuppose that equation  on the iu and v as follows:If t) as in , 3.15),,\document) as in , and (3.t) as in , respectt) as in  in Theort) as in  remains t) as in , we knowombining  and ,,N such tous that  in TheorThe case for In this section, we give some examples to illustrate the applications of the asymptotic dichotomy proved in the previous section.Consider the fourth-order delay differential equationequation , we see It is easy to verify that equation  satisfieHence condition  in Theorequation  which isConsider the fifth-order delay differential equation in the following:equation , we takeIt is easy to verify that equation  satisfieondition  in Theorondition  are osciequation  which is


Diagnostic and statistical manual of mental disorders (DSM). Many have called for a ‘paradigm shift’ away from a medical nosology of diseases toward clinical psychology’s own taxonomy of clinical psychological problems (CPPs), without being able to specify what is to be listed and classified.A taxonomy of the objects of study, theory, assessment, and intervention is critical to the development of all clinical sciences. Clinical psychology has been conceptually and administratively dominated by the taxonomy of an adjacent discipline – psychiatry’s clinical psychological problems in which active PMCs require clinical intervention, and psychopathological problems which are unlikely to be ‘cured’ by PMC-breaking alone.An examination of DSM’s problems for clinical psychology, especially its lack of clinical utility, and a search for the essence of CPPs in what clinical psychologists actually do, leads to the proposal that: The critical psychological-level phenomenon underlying CPPs is the occurrence of ‘problem-maintaining circles’ (PMCs) of causally related cognitions, emotions, behaviours, and/or stimuli. This concept provides an empirically-derived, theory-based, treatment-relevant, categorical, essentialist, parsimonious, and nonstigmatizing definition of CPPs. It distinguishes psychological problems in which PMCs have not (yet?) formed, and which may respond to ‘counseling’, A subsequent classification and coding system of PMCs is proposed, and expected benefits to research, communication, and the quality of case formulation in clinical psychology are described, reliant upon a development effort of some meaningful fraction of that which has been devoted to the DSM. The focus, advancement, and direction of any scientific discipline is critically and essentially dependent upon the basic conceptualization that it holds of its subject matter –3, and uremedial discipline – may most simply be called clinical psychological problems (CPPs). CPPs have, over time, variously been conceived as instances of demonic possession  shift and sway like in no other area of medicine” . The DSMWhen arbitrary categories are forced onto dimensional phenomena like symptoms, then both reliability and validity have been shown to suffer –70. Not This conceptual vacuum has left ‘mental disorders’ as merely social constructions , ‘open ccategory else they revert, like mental disorders, to being merely dimensional variants of normality reaThese changes of direction embodied in the soon to be implemented ICD-11 are a response to the recognition that psychotherapeutic interventions are often transdiagnostic . HoweverHowever, clinicians and clinical researchers generally require a categorical approach  because statistical significance of a relationship or an outcome, but categorical approaches tell us more about their clinical significance – whether a qualitative difference has been created or detected, or merely a possibly-trivial change in one psychometric score.For our purposes, the cutpoints and criteria for the determination of the presence of a CPP must be clearer, better validated, and more essentialist than those for the diagnosis of mental disorders. Dimensional measures give us indications as to the The usual structure of research projects in this field has been to explore the relationships between dimensional constructs and factors, such as ‘anxiety sensitivity’, and categorical problems, such as generalised anxiety disorder (GAD)  even thoprocesses than psychopathological conditions. For example, Melville et al. ),ference ( p.157).“There are undoubtedly many functionally distinct subtypes of patients currently mixed together in popular diagnostic systems” ( p.971). A major motivation of the HiTOP consortium has been the fact that randomized controlled trials (RCTs) rarely show superiority among thoughtfully conceived treatment packages , and thamultiple (diagnostic) criteria. The resultant composite correlation will be an average of the correlations with each of the dimensions or criteria, each of which could correlate quite weakly with the others.This problem has been thoroughly outlined by Smith, McCarthy, and Zapolski , who havThe power of RCTs is seriously compromised when the groups that subjects are randomized into are vaguely or spuriously defined. “With heterogeneous treatment effects, the ATE [average treatment effect] is only as good as the study sample from which it was obtained” . This isIt will be of much greater benefit when we are able to assemble research results into clinical guidelines not on ‘the treatment of Depression’ or ‘of Bulimia Nervosa’, but on psychological interventions with CPPs A and B, defined by mechanisms, which may cross diagnoses or differ within a diagnosis. For example, we know that targeting specific mediating cognitive processes in a social phobia is more effective than standardized generic cognitive-behavioural treatment , becausepsychological-level one ; (b) Psychologically theoretically rich and evidence-based; not a postmodern ‘categories-by-convention-only’ model. It must define an essence. If it comprises a ‘harmful dysfunction’ , then its harmfulness must be a matter of subjective judgement, but its dysfunction must be defined objectively; And according to only one or two criteria, not a hodgepodge of them; (c) Categorical, rather than merely dimensional; (d) Encompassing of all problems currently appropriately and successfully addressed by clinical psychologists; not merely diagnosed mental disorders; And (e) better at avoiding the stigma and responsibility-confusion problems which have been exacerbated rather than ameliorated by the disease model.A new conception of CPPs must therefore be: (a) A By examining what clinical psychologists actually research and address in their clinical practice, we have come quite close to uncovering the essence of CPPs. Thus far we are clearer about what constitute ‘psychological problems’.remedial discipline. To remedy is to rectify or make good, to cure or heal, to put right or restore, or to counteract or remove. Therefore the new taxonomy will list problems – negative ‘states of affairs’ that are undesired, aversive, inappropriate, maladaptive, or dysfunctional. This loose listing of potential criteria is an indication that the ultimate judgement as to what constitutes a ‘problem’ will inevitably be largely subjective and value-laden, based on ‘presenting problem’ (the client’s standpoint), social norms (society’s standpoint), or psychometric measures (the therapist’s standpoint). Unlike mental disorders, CPPs will not be of their nature problematic. They will have to be deemed problematic.Clinical psychology, like forensic psychology or clinical neuropsychology, is an applied psychological level of analysis. That is, at the level of stimuli, cognitions, emotions, and behaviour. Therefore, the new taxonomy to be proposed will not be a listing of biological dysfunctions or of problems faced by communities, cities, nations, or the human species. Sociologists and anthropologists can work at such taxonomies.CPPs are by definition at a It may include, however, problems at an interpersonal, couple, or family level. Clinical psychology has studied these, and does provide remediation at this level. In this respect CPPs are further distinguished from mental disorders, because the biological level of analysis, which DSM’s mental disorders aspire to, is conceptually as well as practically discordant with relationship problems. Very few would recommend that we medicate a faltering relationship.clinical? That is, what makes them warrant interventive clinical psychological therapy? If a taxonomy of CPPs is to be treatment-relevant, then not only will different CPPs imply different treatments, but the very definition of a CPP will include a criterion of being treatment-worthy.But what makes psychological problems clinical? Is it simply a matter of degree – a dimensional criterion? Or can it be categorical – a qualitative criterion?To feel sad is a negative psychological-level state of affairs – a psychological problem. But it can also be an appropriate, constructive, natural, ‘healthy’, adaptive, or functional problem to have, as in normal grieving. What determines when this state of affairs warrants intervention? When does it become Table Studies of the extremely common negative situations or reactions listed in Table process occurring – not the ‘symptoms’ or their severity – will determine whether a CPP is present and intervention is warranted. This criterion can be categorical: Either an undesired, harmful, or dysfunctional process is occurring, or it is not.What is the essential difference between a person in a depressed state, perhaps experiencing a grief reaction, and a person whose depressed state justifies, and can benefit from, interventive therapy? A person experiencing a natural, healthy grief reaction following a bereavement  can present phenomenologically quite severely. She may tick most of a symptom list. This cannot therefore define a CPP, as she may well be following a natural course toward resolution (as the majority of bereaved people do). That is, the a mechanism or process of maintenance, which can be discovered through functional analysis or case formulation, and which then requires and justifies  psychological-level intervention or therapy to disrupt it.Therefore, the essence of CPPs lies in The overwhelming majority of people who experience the grief of loss emerge from this process without clinical intervention , 168. Buprocesses that are natural and usually successful. Could complicated grief [process? Especially one that is cyclic and self-perpetuating rather than linear and progressive. This would explain why routine intervention for bereavement is not generally recommended, and “may interfere with ‘natural’ grieving processes” .What is the necessary and sufficient condition that can distinguish a person simply experiencing anxiety from a person with a clinical anxiety-related problem who can benefit from interventive therapy? A comparison between an acute stress reaction and Posttraumatic Stress Disorder (PTSD) can illustrate this difference.Around 60% of men and 50% of women will experience one or more significantly traumatic events in their lives , 176. ExAcute stress reactions are unpleasant, and so they are a ‘psychological problem’. However, they generally fade over time  and mostBecause DSM diagnosis is symptom-profile-based, and many people experience severe symptoms in the immediate aftermath of trauma, DSM has defined an interim disorder – Acute Stress Disorder (ASD). However, around the same proportion of trauma survivors with or without ASD symptoms – with other symptoms or with sub-clinical symptoms – can go on to develop PTSD . Also, tIt is no coincidence that two of the most recommended treatment elements for PTSD are prolonged in vivo exposure therapy and imaginal exposure to flashbacks . With remaintenance processes that can occur in the aftermath of a trauma. If, on the other hand, treatment is directed at symptoms, then this can interfere with adaptive processes. Critical Incident Stress Debriefing (CISD) and other such proactive interventive treatments administered early in an acute stress reaction have been found to be ineffective, or even counterproductive, in the prevention of PTSD [Such a summation of this research shows that the development of PTSD from an acute stress reaction is a function of  of PTSD , 193–197 of PTSD .maintained. This process of maintenance, if it occurs at a psychological level, and so is amenable to psychological-level intervention, is then what ‘causes’ and defines a CPP. “Self-perpetuating vicious circles” have been found to explain the persistence of “symptoms” not only in grief and bereavement and in PTSD, but also in anxiety states, panic syndromes, obsessive problems, and depression [This critical maintenance criterion for CPPs holds that psychological problems such as sadness or anxiety (problematic emotions), preoccupations or obsessions (problematic cognitions), or classroom disruptive behaviour or frequent handwashing (problematic behaviours) see Fig.  will, bepression .Fig. 1ThTherefore, the essence of a CPP lies in some form of psychological-level maintenance process. Inasmuch as a treatment needs to address the ‘true cause’ of a CPP, the relevant maintenance process should also indicate appropriate therapeutic intervention. . However, the case formulation approach has led much more to tailored, individualized treatments based on idiosyncratic, but evidence-based, case conceptualizations . The DivCase formulations in clinical psychology are developed within many alternative theoretical orientations. Any new conception, and hence taxonomy, of CPPs will need to accommodate all evidence-based models of CPPs. It will need to be, in that sense, a meta-theory.However, for present purposes, in our search for an essence to CPPs, the process of case formulation within behaviour therapy and within CBT will be examined initially.The ‘functional analytic clinical case models’ of behaviour therapy were developed as a clear and parsimonious way to organize the variables and relationships in a functional analysis . In the complex network approach “disorders are conceptualized as systems of causally connected symptoms rather than as effects of a latent disorder” . Tmptoms” ( p.140). mptoms” ( p.96). Cmptoms” ( p. 139).This entirely new way to conceptualize CPPs is already heavily research-based (e.g. ) engendebetween people, as when a child’s sleeping problems produces parental sleep problems; both feed into behaviour problems, which then increase parental stress, and which does no good at all for the parents’ management of the child’s sleep problem . And networks – like diagrammatic case formulations – imply intervention points. The ‘centrality’ of a symptom in a network refers to how causally connected and hence clinically relevant it is. It is recommended that one target in therapy the most central symptoms .How many symptoms need to be “on” to call a problem a CPP? And how severe do they have to be? No essence to mental disorders is stipulated.However, the network model does not as yet offer us a new conceptualization – a new “essence” of the common psychological disorders . Until varise from or result from the causal interplay between psychopathological symptoms [This falling short (until very recently) of offering a new conceptualization of CPPs is attributable to the network approach’s assumption that mental disorders and psychopathology symptoms . So in tself-sustaining in feedback loops that become ‘stuck in a disorder state’. Borsboom [Borsboom  and BorsBorsboom  describeAnother major problem for clinicians with the network model to date is its complexity. Not only are there disagreements over the reliability of the general and theoretical results of network analysis methods (see  versus ), but inWhat if, in “defining our disorders at the level of property clusters under-girded by dysfunctional but self-sustaining mechanisms” ( p.1149),So both the transdiagnostic movement and the network model have moved focus from symptom measurement and diagnosis to the case formulation of problem-maintaining processes. But no replacement conception and subsequent problem taxonomy or functional classification system has yet ensued .The major drawback of psychological-level case formulation of CPPs when contrasted with the diagnosis of mental disorders is that functional analyses or case formulations can be complex, vague, and idiographic ( p.1153).Superimposing a transdiagnostic dimensional model over a categorical diagnostic nosology (e.g. ) merely Therefore, what is required is some form of simplifying “linchpin”  which coAssembling the criteria developed thus far, the items to be listed in the new taxonomy of CPPs must be: Problems, formulated at a psychological level, that warrant therapeutic intervention, and rest on an empirically-supported, theory-rich model, which parsimoniously and categorically defines processes or mechanisms that exist in the real world, are causally maintaining and hence treatment-relevant, simplify complexity, and aid in case formulation. It is also desirable that such listed CPPs can generate and organize treatment-relevant research, are codifiable, will minimize stigma, include relationship problems, and recognize and distinguish various ‘kinds’ of problem.So, having loosed ourselves from the conceptual manacles of the mental disorder model of CPPs, we now find the requirements imposed upon our new conception to be much more exclusive and demanding. But one notion can satisfy all of the above criteria…..problem-maintaining circle (PMC) of psychological-level causal elements, several illustrations of which are presented in Fig. essential difference between a negative psychological-level state of affairs , and a state of affairs requiring interventive treatment – a clinical psychological problem (CPP) , then intervention is justified. The identified mechanism of perpetuation or maintenance will then indicate points of intervention, and hence particular therapies.To be upset (e.g. an acute stress reaction) is negative and psychological, so it is a ‘psychological problem’, but this does not warrant referral, formulation, and therapeutic intervention, until it persists or becomes self-maintaining (e.g. PTSD) through a process or mechanism which, when identified, can also indicate which treatment to apply. This mechanism then is the essence of, and defines, the CPP.different elements of the tripartite model, as when Thought A leads to Feeling X, which leads to Thought A (“Life is awful” ➔ sadness ➔ “Life is awful”).The simplest expression of a PMC would be a bidirectional causal relationship between two features within one element of the tripartite model of Fig. Since people are innately complex, many PMCs will involve several elements of Fig. If a full PMC does not form, the psychological problem  will likely resolve, remit, dissolve, or be processed. For example, Bill and Mary have a screaming row. Tomorrow, Bill apologizes and life goes on. If, however, Bill wakes tomorrow still angry, ignores Mary over breakfast, she sees and resents this, there is no intimacy all week, both blame the other, her respect for him decreases, etc., then one or more PMCs have formed, and the situation qualifies as a relationship CPP which would benefit from therapeutic intervention, as it is unlikely to spontaneously remit soon.The description of a forming PMC can start at any element of Fig. prevention of CPPs, but is largely irrelevant once PMCs have formed. This is the reason that all recommended evidence-based therapies happen to focus on problem maintainers rather than require analysis of presumed distant historical precipitants.Generally, historical etiology of a CPP is identified in the ‘Events, Situations’ element. Common examples of such include past traumas, parenting styles, recent traumas, and stress accumulation. However, it is just as possible that ‘Feelings’ or ‘Behaviours’ or ‘Thoughts’ could “go wrong” first. Examples could include a spontaneous panic attack (a Feeling) leading to Panic Disorder, PTSD that forms from an acute stress reaction due to coping by avoidance (a Behaviour), or health anxiety that becomes problematic due to catastrophic thinking (a Thought). What “went wrong” first may be important in the The elements in a PMC can be specific, such as a particular thought, or general, as in an abiding attitude . They caFor example, the ‘Feel depressed’ PMC of Fig. By definition, a PMC formulation that explains the maintenance of a CPP must indicate at least one intervention point, and hence imply a known therapeutic procedure which targets this, or at least invite research into effective interventions at such a point.A PMC taxonomy is clearly transdiagnostic. Some PMCs occur within the symptom network  of what between the symptom clusters of traditionally distinguished disorders. They involve ‘bridge symptoms’, in network terms. Figure However, many empirically discovered PMCs occur The voluminous and clinically valuable literature uncovering causal relationships between symptoms , whetherThe PMC model of CPPs replaces the seven-or-more criteria for the existence of a mental disorder found in DSM, with one criterion: Has a psychological-level PMC formed? The nearest DSM criterion to this is duration of the problem. However, this is an inadequate criterion because the complexity of life means that some PMCs can form and warrant intervention in days, and some do not cement for months, even years. Sleep problems deserving of psychological-level intervention can form in days. If a person has a disrupted night for any reason, and then is kept awake by the anxious anticipation of another terrible night, a PMC has formed in 2–3 nights that can perpetuate or even spiral. Intervention to break this PMC may be warranted and successful even on Night 2.On the other hand, the cognitive, affective, and behavioural changes that are expected, and possibly necessary, after the death of one’s lifelong spouse may persist for a year or longer, during which time a clinician would be loath to interfere lest the bereaved’s natural coping and recovery processes be disrupted ( p.140). When the subject matter of a scientific discipline has been determined and defined, the process of study will begin descriptively, with systematic observation and listings . From su“A reliable system of classification is important for the advancement of a clinical science” ( p. 386) Therefore, the development of the most appropriate taxonomy of CPPs is essential for progress in clinical psychology to enable research to produce general laws and rules, to provide a common language for the reliable assessment of problems, to simplify communication, to codify problems for third-party payers, to enable relevant reliable research conclusions, to suggest problem causes, to optimize and tailor treatments, as well as to develop new ones, to inform and ease the minds of sufferers, and to organize access to services, benefits, or support groups , 53. AllBut it has done this poorly because, though greater specificity and description of symptoms at a phenomenological level has at least given us a common language that can be applied with reasonably good interrater reliability , 247, beWhile the British DCP has been calling for a conceptual paradigm shift , across The current state of psychological science has been compared to that of physics 200–300 years ago, in that, despite voluminous research over the past 60 or so years, it is still plagued by theoretical disunity, which is largely a consequence of the non-standardized use of terms by researchers and clinicians in their theoretical orientation silos . This diAs with clinical psychology’s own conception of CPPs, the nature of its own taxonomy of CPPs can be derived from: (1) DSM’s inadequacies; And (2) clinical psychologists’ natural taxonomic focus and categories.conception of CPPs apply to its taxonomy. Its items  are conceptually biologically based, not psychological-level processes. They have no psychological  essence, and so definition and classification are only descriptive, not explanatory, and diagnosis is minimally treatment-indicative.With regard to (1) DSM’s taxonomic inadequacies for clinical psychology, all of the problems with DSM’s Due to its medical model basis, DSM diagnosis does not even tell us when to intervene medically  and when to intervene at a psychological level (e.g. with a CBT), let alone whether to intervene psychologically by first addressing a person’s situation, and/or their thinking patterns, and/or their behaviour, and /or their feelings states.Furthermore, several types of CPPs  are not included. The stigma of a DSM diagnosis of ‘mental illness’ is barely less than that of ascribing moral weakness or sinfulness or demonic possession. And research based on DSM categories has not been able to find systematic or explanatory links between psychosocial treatments and problem types. These are the problems that a new PMC-based classification of CPPs must, and can, overcome.Further, a new taxonomy of CPPs, based on a new conception of CPPs, must be: (a) an aid to case formulation, case conceptualization, or the functional analysis of behaviour; (b) a listing of processes or mechanisms, rather than states, conditions, or diseases; (c) a recognition of and distinction between various conceptual kinds of psychological problem, such as between ‘clinical’ versus ‘normal’, ‘psychopathological’ versus ‘psychological’, ‘organically-based’ versus ‘functional’, etc. (d) relevant to  treatment choice; and (e) usable in place of diagnostic groupings in research on psychotherapy outcomes.With regard to (2) clinical psychologists’ natural taxonomic focus and categories:within the taxonomy (which treatment for which CPP?) and the borders of the taxonomy  must be defined by this criterion. Thus far CPPs have been distinguished from other psychological problems  and predominantly functional  problems. “The current classification systems are less controversial for conditions with an identified biological aetiology such as in the fields of neuropsychology, dementias, and moderate to severe learning disability” ( p.2).Because biochemistry underlies all psychological activity .clinical utility of the candidate levels of analysis and of intervention that should determine whether a problem is best regarded as a ‘psychopathological problem’ or a CPP. Therefore, are there problems that are better considered – either in therapeutic terms or in explanatory-mechanism terms – as essentially organically-based rather than entirely PMC-driven? Haslam [It is the ? Haslam  has arguFurther examples of problems that are difficult to account for in a purely symptom-network model  include From a treatment perspective, some problems respond better to pharmacotherapy than to psychotherapy. For example, APA’s  practiceTherefore, although CBT-based family therapy and stress management have been found to reduce the incidence of readmission with schizophrenia , 259–262each relevant level.Therefore, PMC theory seeks to distinguish problems best regarded as psychological-level, or psychopathological, or psychiatric, or neurological, or sociological, and so on, and promotes concept definition and an appropriate problem taxonomy at additional, concordant, and complementary body of concepts and therapy-relevant taxonomy.Another consequence is that the common language of ‘mental health’ services is anticipated to remain that of ‘mental disorders’. This conception has dominated for a long time, and is arguably the most appropriate for a substantial portion of people’s problems. PMC theory and its conception of CPPs is likely to remain an Table It must be noted that these two criteria - likely mechanism and first-line therapy - are not always consistent with each other. There are some Type III conditions for which the current best practice treatments are psychotherapies, simply due to the lack of advancement in the biochemical or neuropsychological understanding and control of the problem. Examples.would include DSM’s Premenstrual Dysphoric Disorder, which, though assumed to have an organic basis, is better ameliorated by CBT –265 thanIt is quite possible that problems will move between Types II and III classifications as psychological-level or neural-level underlying mechanisms are discovered and new treatments are developed. Again, though, these two criteria are separable. For example, neural mechanisms underlying OCD and PTSD are being uncovered –278, butThe DSM, being based on an atheoretical pragmatic model, both poorly defines the limits of its taxonomy , and arbitrarily categorizes its contents . The lack of a defining essence to mental disorders means that, unlike the PMC-based distinction between mundane psychological problems (Type I) and CPPs (Type II), the DSM does not tell us when to treat.But within its taxonomy DSM also regards all of the following as examples of the one ‘kind’ of thing: A bereavement reaction, a spider phobia, OCD, antisocial personality disorder, schizophrenia, autism, and frontal lobe syndrome. They are all equally ‘mental disorders’. This absence of theoretical discrimination spreads the stigma of mental illness widely, gives no guide to subsequent treatment, or to research direction, and results in unending disagreement as to kinds, categories, or classes of problems, meaning that each iteration, up to and including DSM-5, has announced major reorganizations of internal structure.The ultimate goal of classification is its connection with treatment , 35, 279However, treatment relevance is only one element of the clinical utility of a taxonomic listing. Clinicians will use a taxonomy of CPPs for other purposes such as input to case formulation, for administrative, insurance, or legalistic purposes, to assist in communicating clinical information, the use of categories in clinical practice, and predicting future clinical management needs ( p.947). case formulation and subsequent tailored treatment programs.If classification within the taxonomy were to be according solely to specific treatment implications, this would result in categories such as “Problems treatable by exposure therapy” or “CPPs for which thought stopping is frequently a useful adjunct”. Such categories would be large, unwieldy, highly overlapping, and counterintuitive. Also, this would be a reversion to the medical model ‘pill for an ill’ or ‘Condition X therefore Treatment Y’ approach, rather than increasing the rate, reliability, and communicability of The phenomena of divergent trajectories and multifinality  mean thaDSM has been criticized for ignoring the spontaneous consensus models of the clinical community . ExtensiThe ‘folk taxonomies’ of eclectic clinicians are quite consistent across theoretical orientations and professions , 289, anWhen PMCs are grouped under presenting problems such as ‘Depression’ or ‘Anger problems’ , then hoThe HiTOP consortium  has reveTherefore, it is proposed that PMCs be grouped in the new CPP taxonomy for clinical utility under generally-accepted well-understood presenting problem headings such as ‘Anxiety problems’, ‘Depression’, ‘Relationship problems’, ‘Eating/Weight Problems’, and ‘Substance abuse/dependence’.A nascent micro classification system of PMCs is already in clinical use and is taught in several postgraduate clinical programs , 221. Hopresenting problems (e.g. depression), including Type III psychological problems (e.g. schizophrenia), and ‘Interactive clinical psychological problems’, currently labelled as ‘comorbid conditions’ (e.g. chronic pain & anxiety). Then ‘y’ codes represent the major classes of problematic underlying maintaining mechanisms commonly identified in several presenting problems (e.g. hypervigilance). And ‘z’ codes represent specific evidence-based mechanisms which imply specific treatment approaches .However, in the interim, a proposed classification and coding system is presented in For example, the PMCs illustrated in Fig. Such a framework can systematically summarize and stimulate the currently disparate streams of research on assessment, case formulation, and therapeutic intervention in clinical psychology. For example, instead of assessing the efficacy of a particular Cognitive Therapy package in helping a diagnostically uniform  sample of sad people, subjects could be selected based upon identification, through an assessment and case formulation, of the presence or functioning of PMC 2.2.3 above. Such would be infinitely more logical, and just as methodologically sound in a randomized controlled trial.CBT’s substantial evidence base, and its inherent emphasis on here-and-now case formulations and therapeutic disruption of problem maintainers, make it a natural fit for the PMC model of CPPs. For example, the dimensional models being developed by the HiTOP consortium are particularly compatible with CBT approaches . They arHowever PMC theory is not specific to a CBT view of the world. The Complex Network Model of CPPs, which PMC theory has grown from, “does not involve the acceptance of any particular theory about psychopathology” ( p.96). HFor example, the movement toward integration of models of psychotherapy , 294, hapresence of a disorder can be determined by “cyclic psychodynamics” [Within the psychodynamic model the type of problem or disorder can be gleaned by content, but the ynamics” –299. Narynamics”  p.52). Synamics” .Family systems theorists have long emphasised cyclical formulations with psychodynamic elements . Indeed Nor is defining the essence of a clinical problem in terms of vicious circles or PMCs particular to clinical psychology. It has been proposed or enacted within forensic psychology , 304, orTherefore, theorists and researchers from many theoretical orientations are able to contribute, and to utilize, the new taxonomy, only providing that the focus is on problem maintenance, and the relevant PMCs and implied treatments are evidence-based.oversimplified them.A PMC taxonomy overcomes almost all of the problems clinical psychologists have with DSM. Its only comparative drawback is its relative complexity. But we have seen that, for clinical psychologists, DSM’s simplicity has been gained at an unacceptable cost to its validity and clinical utility. Life is complex. People are complex. And DSM has Unlike DSM, a PMC taxonomy does not claim that the items it lists are inherently negative. It simply lists discovered cyclic causal sequences. Whether they are viewed as desirable or undesirable is a value judgement. There are as many ‘virtuous circles’ as there are ‘vicious circles’. DSM’s controversial conceptual overreach in asserting that, for example, homosexuality or Female Orgasmic Disorder are inherently negative  is thus avoided.mechanisms or processes that must be addressed. DSM’s problems with multifinality and divergent trajectories are also thus overcome.Psychologists do not simply attempt to alter states or reduce ‘symptoms’. They do not merely work to cheer up a sad person or to relax an anxious person. The PMC taxonomy lists problematic ongoing underlying clinical psychological problems as perpetuating cyclic processes. This simple intuitive concept at once confers an essence to CPPs, that is parsimonious , categorical not dimensional, and has intrinsic clinical utility and treatment-relevance.A PMC taxonomy defines and lists informative. It tells us much about the person involved. Anxiety PMCs are historically invariant. We know of phobic PMCs from Roman times. Such problems are discrete. There are definable boundaries. They are uniform. People trapped in eating problem PMCs have many similarities. They are, by definition, immutable. They rarely spontaneously remit. There is one necessary feature . They are inherent; there is a sameness under the symptoms. And they are natural, and not simply an artificial product of people’s efforts to classify made-up mental disorders.CPPs, as defined within the PMC model, qualify as essential entities on the eight criteria of such proposed by Haslam and Ernst . The idetheory-based, be this PMC theory or evidence-based clinical theory. But, given the cyclic nature of scientific research and theory construction, the taxonomy can improve the focus and organisation of research efforts, and the reporting and assemblage of research results.A PMC taxonomy is communicate more psychologically-relevant and treatment-relevant information than can DSM’s. “Bill Bloggs has been experiencing PMCs 2.3.1 and 2.4.1 for approximately 6 months” is much more psychologically informative – it tells us much more about what has gone wrong and what to do about it – than “Bill Bloggs has been suffering a Major Depressive Disorder for approximately 6 months”.The proposed PMC coding system can Communicability will be enhanced not only among clinical psychologists. The medical model and PMC theory are compatible and complementary. Already, clinical psychologists accept referrals of diagnosed mental disorders, understand what is meant, do their own functional analyses and case formulations, and often feed these back to the psychiatric or physician referrer, who understands them perfectly well, and may even appreciate a PMC code summary of this formulation.case formulation as well as its communicability through standardization of nomenclature. A PMC-based model is also very comprehensible and communicable to clients. Quite complex graphically presented individual case formulations can be simplified, standardized, and described by separating out the individual PMCs involved.A taxonomy of PMCs can increase the reliability of stigmatizing than being conferred with a diagnosis of a psychopathology or mental disorder.A person who is offered a PMC-based case formulation of their CPP with its explained mechanisms, treatment implications, openings for self-help, and overlap with normality is likely to find this more comprehensible, more optimistic, more empowering, and less Within the model different ‘kinds’ of psychological problem are recognised and operationally defined  control group .Fairburn et al.’s  transdiaSo, when case formulations are used to guide treatment rather than clumsy, theory-bereft diagnoses, indications to date are that the subsequent tailored treatments improve our effectiveness. The next step appears to be to improve the reliability, standardization, and validity of case formulation and treatment selection by basing therapeutic trials and outcome studies on PMC-defined rather than DSM-diagnosed experimental groups.The Division of Clinical Psychology of the British Psychological Society is one of many bodies that now “believes there is a clear rationale and need for a paradigm shift in relation to functional psychiatric diagnoses” ( p.5). HoIt is proposed that the next logical step in the scientific development of the discipline of clinical psychology is the formation and dissemination of a taxonomy of CPPs based on its own conceptual scheme and operating primarily at a psychological level. The independent conceptual, research, and clinical development of the profession has advanced sufficiently for this critical step. In fact, it is overdue; seemingly delayed by the hegemony of another profession’s corresponding taxonomy – psychiatry’s nosology of mental disorders. Benefits to the interactive process of theory development, empirical research, and clinical practice (itself a ‘virtuous circle’) will ensue.The proposed taxonomy comprises a listing of psychological-level problem-maintaining circles (PMCs) that distinguish and explain the critical difference between transient, linear, negative psychological  events, states, reactions, or experiences , self-perpetuating psychological-level causal loops (CPPs) that warrant, and can be affected by, psychological-level therapeutic intervention (Type II), and problems that can persist even when psychological-level maintainers are nullified .DSM-IV Sourcebook [The development of the various iterations of the DSM has involved the assignment and coordination of vast numbers of contributors, panels, committees, and task forces. For example, three of the five volumes of the urcebook  alone courcebook . Furthercause negative feelings, thoughts, or behaviour via vicious circles, such as through instilling shame or hopelessness ” (DSM300.23) actually exists. There are no reliable or validated biological markers or criteria or measures outside clinical psychological judgement that can detect this ‘illness’. It is defined by its effects, which are attributed to its existence . It is aessness ( p.69).)evidence-based model of a CPP, which in turn directly implies therapy choice. It is treatment-relevant, not by way of indicating which pill, or even which monolithic 12-session therapy package, can ‘cure’ the ‘Excessive, problematic social anxiety’, but by suggesting a specific Cognitive Therapy intervention to address the distorted self-evaluation of social performance – to break the PMC at that point.On the other hand, bountiful supportive evidence has emerged for the real-world existence and operation of the psychological-level PMC: Excessive, problematic social anxiety ➔ Overly negative evaluation of one’s social performance ➔ Unreasonable persistent regrets over social contacts ➔ Excessive, problematic social anxiety. There is psychological-level evidence for the existence and operation of every one of these causal links. In fact such evidence led to the development of this model. It is an The proposed new taxonomy of CPPs is therefore theory-based, treatment-relevant, evidence-informed, and pragmatic. Much research required for its development has already been undertaken. It is now a matter of framing the results (e.g. the evidence-based models of psychopathology) in PMC terms, extracting the smallest simplest units (PMCs) and listing them under generally-useful clinical categories of presenting problem. This task deserves an effort corresponding to some meaningful fraction of that which has been devoted to DSM’s development, promotion, and dissemination.The independence and standing of the discipline and profession may then be restored, and, more importantly, the millions of people experiencing crippling CPPs may be offered more therapeutically relevant, less stigmatising, more empowering, more evidence-based, and more comprehensible, reliable, and systematic formulations of their problems.Many uncertainties will remain despite such a clarifying taxonomy. Disagreements will continue as to whether a particular problem is best regarded as a Type I, Type II, or Type III psychological problem. This has long been a conceptual issue , a research-informed therapeutic issue (e.g. counselling versus CBT versus pharmacotherapy), and a territorial/political issue among the professions. A PMC taxonomy can at least clarify the conceptual issues, and guide research to address the therapeutic issues.